ASMR Teaching You Prenatal Genetics | Meiosis, NIPT, Chromosome Conditions, Carrier Screening

本站添加: 2026-05-07

[00:00:00]Hello. I'm happy to have you here.

[00:00:03]Welcome back to my channel and welcome to a new teaching you genetics video.

[00:00:10]It's been a long time since I've done one of these.

[00:00:14]They do take like a good bit of prep and I feel like I've covered so many different topics. So, it's kind of hard to keep putting them out there.

[00:00:24]And a lot of times they don't do super well, but I love that the people that watch them seem to really like them. So, I I love to keep doing them.

[00:00:32]Um this one is going to be like prenatal genetics focused.

[00:00:39]I have kind of done one of these at the end of each of my genetic counseling rotations because I'm finishing up genetic counseling school. Um and prenatal was my last rotation. I just finished it up last week. And so, I'm going to go through some of the things that I learned in prenatal genetics.

[00:01:02]Um so, we will talk about meiosis and chromosome conditions and the screening that's done for that during pregnancies and then also carrier screening and some like recessive conditions. So, this should be fun. We'll see how it goes.

[00:01:20]And yeah, I hope that you enjoy and I hope that you learn something.

[00:01:26]Okay.

[00:01:27]So, I'll just start with like the first thing that I learned in prenatal genetics.

[00:01:33]Um and it's something that I always check for. It's like the first thing I write down about a patient when I'm prepping for a session for an appointment. And that is their pregnancy history. So, we call it the Gs and Ps. Um what are their Gs and Ps?

[00:01:55]And it basically just says what their whole pregnancy history is. So, how many times they have been pregnant, what the outcomes of each of those pregnancies were.

[00:02:07]So, the G part of Gs and Ps is the gravida.

[00:02:14]And that is the total number of pregnancies that someone has had.

[00:02:20]Um so, if you've been pregnant and you had a miscarriage, you had a living child, you had no matter what the outcome was, that's your G. It's the total number of pregnancies.

[00:02:33]And then, the P is the parity, which is the number of living children.

[00:02:42]So, um if you have been pregnant twice and you have two children, you are G2P2.

[00:02:51]Two pregnancies, two living children.

[00:02:54]G2P2.

[00:02:55]Um yeah.

[00:02:58]P The P part can be broken down further, especially if like the G and P doesn't match. So, if you're G4P4, we would assume pregnant four times, four children.

[00:03:14]Um but that's not always the case. Like there are different types of outcomes that can happen during pregnancies.

[00:03:20]And so, this is the kind of breakdown of that P number.

[00:03:28]So, it's we would say GTPAL.

[00:03:32]So, total number of pregnancies and then TPAL is the breakdown of what the outcomes were.

[00:03:41]So, T is term deliveries. So, that's deliveries of children past 37 weeks of gestation.

[00:03:53]Um so, 40 weeks is considered like full term. Like that's what your due date would be is 40 weeks gestation. Um anything after 37 weeks is considered term, full term.

[00:04:08]Um the P is preterm deliveries. So, um any deliveries before 37 weeks of gestation is preterm or premature.

[00:04:21]Um A is abortions.

[00:04:25]Um so, the number of abortions that someone has had. Um fun fact, a miscarriage is considered a type of abortion. It is just a spontaneous abortion versus an elective abortion. So, abortion doesn't necessarily mean that you chose to end the pregnancy. Um abortion just means the removal of a fetus from the womb. Um whether that was against your control or a decision that you made.

[00:05:03]Um yeah. So, the A number incorporates spontaneous or elective abortions.

[00:05:12]And then, the L is living children. So, children that are living um that lived past the like neonatal period.

[00:05:25]Um yeah.

[00:05:27]So, when you're looking at someone's Gs and Ps, there will be the G number in blue.

[00:05:35]And then, you'll have P and then the four numbers, the TPAL.

[00:05:41]TPAL.

[00:05:43]And so, you just have to know that that's what these numbers stand for is the the TPAL.

[00:05:50]So, let's go through some examples.

[00:05:53]So, our first one we have G1 P0000.

[00:06:00]So, if this person has one total pregnancy, zero term deliveries, zero preterm deliveries, zero abortions, zero living children, they are pregnant with their first baby.

[00:06:15]So, one pregnancy, but no children, no pregnancy outcomes.

[00:06:21]They are currently pregnant with their first baby.

[00:06:26]Now, let's look at this one. So, we've got G3. That's three total pregnancies.

[00:06:35]P1.

[00:06:37]So, one term delivery.

[00:06:41]T or P1 is one preterm delivery.

[00:06:48]A1 is one abortion.

[00:06:51]We don't know if that was spontaneous or elective. And then, the last number is a two, meaning there are two living children.

[00:07:03]So, this person had three pregnancies.

[00:07:05]Two of them are living.

[00:07:08]One was term, one was preterm. And then, one was either a miscarriage or an elective abortion.

[00:07:16]So, so, the P numbers aren't going to add up to the G number, but it tells you what all of the outcomes were.

[00:07:28]So, yeah. Okay. So, now let's test you.

[00:07:31]Let's see if you can figure out what these Gs and Ps mean. So, our first one, what does G1P1002 mean?

[00:07:47]A little bit tricky.

[00:07:49]So, we have one pregnancy, one term delivery, no preterm deliveries, no abortions, two living children.

[00:08:03]What does that mean?

[00:08:08]The answer is that it means twins.

[00:08:12]One pregnancy, one delivery, but two living children means that this person had twins.

[00:08:20]Okay, next one. G1P0100.

[00:08:31]What does that mean?

[00:08:33]One pregnancy, one preterm delivery.

[00:08:43]That means that this person has been pregnant once. They delivered prematurely and that the baby has now passed away, unfortunately, because there's a preterm delivery, but no living children.

[00:08:59]So, we would assume that the baby died either during childbirth or shortly after birth.

[00:09:06]Okay.

[00:09:08]G3P1102.

[00:09:19]Three total pregnancies.

[00:09:22]What does that mean? 1102.

[00:09:29]So, this means that this person had a term delivery and a preterm delivery.

[00:09:35]So, they have two living children and they are currently pregnant with their third child.

[00:09:43]Currently pregnant.

[00:09:46]And then, the last one we have G6P4014.

[00:09:57]Six total pregnancies.

[00:10:11]So, this means the person had four term deliveries, and that's their four children.

[00:10:18]They had one either miscarriage or elective abortion.

[00:10:23]And they are currently pregnant with their sixth pregnancy or fifth child.

[00:10:31]Okay. So, those are your G's and P's.

[00:10:33]Just the basics of pregnancy history.

[00:10:38]And now we're going to move on to talking about chromosome abnormalities and how that is screened for during pregnancy.

[00:10:48]And so, I will give an overview of meiosis to start out.

[00:10:54]Um kind of gives us the basis of how chromosome abnormalities come to be.

[00:11:01]Um So, this is showing meiosis. Meiosis is the process that creates eggs and sperm, which make a baby. Um And that is the process where things like Down syndrome, so chromosomal abnormalities, come about.

[00:11:22]Okay.

[00:11:23]So, we've got this main cell. We'll call this a germ cell. So, this is a precursor of egg or sperm. Um We'll say that we're talking about eggs here. So, this is mom's meiosis.

[00:11:42]So, we've got her cell. This cell will have 46 chromosomes. So, I know, obviously, space, I can't draw 46 chromosomes on this piece of paper.

[00:11:55]Um but you have two each of 23 pairs of chromosomes. So, 23 different chromosomes, 1 through 22, and then the sex chromosomes, X and Y.

[00:12:11]And we have two copies of each of them.

[00:12:14]So, you got one copy from your mom, one copy from your dad.

[00:12:19]So, this is just showing two pairs of chromosomes. So, we'll say the top one is like chromosome three and the bottom one is chromosome 21.

[00:12:31]So, these are the mom's two copies of chromosome three and two copies of chromosome 21. And just imagine that all 46 are there.

[00:12:43]I just couldn't draw it.

[00:12:45]So, they're drawn in slightly different colors because they are different chromosomes. So, we'll say like this was the one she got from her mom and this was the one she got from her dad.

[00:12:57]Um and so on.

[00:12:59]And then they're drawn with little bits that are crisscrossed, as you can see.

[00:13:05]Like a piece of green on this one, piece of blue on that one.

[00:13:09]That is because during meiosis, something called crossing over occurs.

[00:13:15]So, your two copies of chromosome, like the one you got from your mom and from your dad, they cross over during meiosis and they essentially like swap some genetic material um between each other and then they separate to form the egg and sperm.

[00:13:37]And that essentially just creates genetic variation.

[00:13:41]Um If it weren't for crossing over, there would be like a limited number of possible children that two parents could create.

[00:13:52]Um If you just directly passed on the exact chromosome that you got from your parent to your child, like there would be a limited number of possible children that you could have. Whereas, we know that there's just an absolutely endless combination and that's because of crossing over and that sharing of DNA.

[00:14:17]And you'll see how that affects the eggs that are created.

[00:14:22]But so, during meiosis one, that's when these, they're called homologous chromosomes, are going to split.

[00:14:33]So, they're going to separate into different cells, different egg precursors.

[00:14:40]So, we can see that this cell got this copy of chromosome three and this copy of chromosome 21.

[00:14:50]And then this cell has the other one.

[00:14:54]the other one.

[00:14:55]So, we'll say this is like the chromosome she got from mom, but with a little piece of the one she got from dad, and so on.

[00:15:03]So, that's meiosis one.

[00:15:06]And then in meiosis two, each of those are going to split. And so, each egg cell is going to get one They're called sister chromatids.

[00:15:21]One copy of each chromosome.

[00:15:26]And so, we see here that this egg got the fully blue and fully pink.

[00:15:33]This one got the two mismatched ones. And then here as well, we have a mismatched one and the fully green and fully orange one.

[00:15:47]So, each of these are eggs that have 23 chromosomes, one copy from each chromosome.

[00:15:56]And then a random egg is selected to be ovulated each month.

[00:16:03]We'll say that this one is the one that is chosen to become a baby.

[00:16:10]And this is our sperm down here. So, dad, these are the same chromosomes. We'll call this to um number three and this one 21, but he's got different colors cuz he's a different person.

[00:16:26]And when those sperm and egg that each have 23 chromosomes combine and fertilize, we now get a zygote and a baby that has 46 chromosomes. So, they've got a replicated version of this one from dad and this one from dad and this one from mom and this one from mom.

[00:16:52]So, you can see how this is now our baby and this is what mom started with.

[00:16:59]So, baby has 50% of DNA from mom, but it's a different combination than what mom had. So, mom had this whole blue one and baby now has the mostly blue, but with little bits of green.

[00:17:19]So, that's how you create children that are completely different from you.

[00:17:23]Um is they have this combination of DNA that occurs from crossing over.

[00:17:30]Okay.

[00:17:31]So, that's how everything works normally. Let's now talk about how things go wrong. Um So, there is something called nondisjunction and that is how we get something like Down syndrome. So, Down syndrome occurs when you have three copies of the 21st chromosome.

[00:17:59]So, you're supposed to have two of every chromosome.

[00:18:02]Down syndrome is where you just have a third one of that 21st chromosome.

[00:18:08]And so, how that occurs is we're going to say this is again mom's egg and these are her two copies of chromosome 21. So, it's essentially just the blue and the green at the top. So, not talking about or I guess the red and the pink, we said that that was chromosome 21. So, disregarding the blue and the green.

[00:18:39]So, that's her two copies of chromosome 21.

[00:18:42]During meiosis one, we'll say that everything happens normally. So, this cell gets one and this cell gets one.

[00:18:52]But then during meiosis two, this cell separates properly. This cell gets one of each of that chromosome.

[00:19:04]This one doesn't happen normally. So, in this case, this cell gets both copies of chromosome 21 and this cell gets none.

[00:19:17]This just happens by random chance that the separation just doesn't occur correctly.

[00:19:26]Um but also, one of the main things we're going to be talking about is the fact that this gets much more common as a woman ages. So, you may have heard um the terms advanced maternal age or you may have heard that it's riskier to have children after a certain age. This process is what happens more frequently as we age.

[00:19:52]And that is what leads to higher rates of things like Down syndrome as you get older.

[00:19:58]That essentially occurs because I feel like not everyone knows this, but women are born with all of the eggs that you're ever going to have.

[00:20:09]You are born with all of your eggs. So, if you are having a child at 40 years old, that is occurring with a 40-year-old egg or more than 40-year-old egg.

[00:20:22]If you're having a child at 20, that's a 20-year-old egg. So, you're having it with a much older egg and what happens is that the eggs are essentially frozen around right here.

[00:20:36]So, when you're born, when a female is born, her eggs are pretty much in this phase and they're sitting there with their chromosomes already ready to go.

[00:20:47]And as you age, essentially the like bonds between the chromosomes and the bonds that allow them to separate properly start to deteriorate or like get less effective.

[00:21:03]And so, the more time that passes as you age, it's more likely for something like this to happen where they don't separate properly.

[00:21:14]Um just because those chromosomes have been sitting there for so much longer.

[00:21:19]Um whereas in males, they're creating sperm all the time.

[00:21:24]Like the woman's egg has been there since before she was even born. The sperm that created you was created like 36 hours before you were conceived. So, there's not that, you know, breakdown of the bonds between the chromosomes. It's just they're new. They're brand new.

[00:21:47]Um So, yeah.

[00:21:50]But so then what happens? So, the green is dad's 21st chromosome. So, that's what's coming from the sperm.

[00:21:59]Down here, we get our typical two copies of the 21st chromosome. We'll imagine that the cells also have two copies of every other chromosome.

[00:22:11]What happens here is that we're not getting any of the 21st chromosome from mom, but we're getting one from dad. So, that would be called monosomy 21, only having one copy of the 21st chromosome and that's not you can't live with one copy of the 21st chromosome.

[00:22:34]So, if this cell was the one that got fertilized and implanted, it would likely result in a miscarriage because you can't you can't live with just one copy.

[00:22:46]But here, we get both of mom's copies and one of dad's. So, now we have three copies of the 21st chromosome, which is trisomy 21 or Down syndrome.

[00:23:01]So, that is how that happens.

[00:23:03]Um It's just a random event. Sometimes it can be inherited. I'm not going to talk about that in this video, but typically a totally random event that gets more likely as a woman ages and um this same process can happen for every chromosome in the body. So, Down syndrome is the main one we think about, but it can happen for any chromosome. It's just that most other chromosome conditions also are not you can't live with them. There are some others that you can, but most of them would be a miscarriage and you would just never know that that happened.

[00:23:49]Um So, I just have this chart to show you that shows how um these chromosome conditions get more common as we age. And so, on this side, we have maternal age. So, like if she's 25 versus 48, 49.

[00:24:14]This shows the chance of a baby with Down syndrome and this shows the chance of a baby with any chromosome abnormality. So, Down syndrome in addition to any other chromosome conditions.

[00:24:31]The reason that there are different numbers for first trimester, second trimester, and live birth is because these chromosome conditions are like I said, often associated with miscarriage.

[00:24:47]And so, the chance that someone in their first trimester is pregnant with a baby with a chromosome condition is higher than the chance to actually give birth to a baby with a chromosome condition because the rate of miscarriage is high. If that makes sense.

[00:25:08]So, the number goes down as we get closer to birth because there's a high chance of having a miscarriage.

[00:25:18]Um you can see that for example, if you are we'll say 30, there's a 1 in 415 chance of conceiving a baby with Down syndrome.

[00:25:34]There's a 1 in 840 chance of actually giving birth to a baby with Down syndrome.

[00:25:44]And a 100 1 in 385 chance of um having a baby with any chromosome abnormality.

[00:25:54]Then if we are 40 years old, there is now a 1 in 56 chance of conceiving a baby with Down syndrome and a 1 in 94 chance of giving birth to a baby with Down syndrome.

[00:26:11]So, that is significantly higher.

[00:26:14]Fun fact, I was born when my mom was 43, which means there was a 1 in 24 chance that she would conceive a baby with Down syndrome.

[00:26:26]A 1 in 13 chance that I would have a chromosome abnormality.

[00:26:33]But I don't. Um so, we got very lucky cuz she was definitely on the older side.

[00:26:41]But yeah.

[00:26:43]Okay.

[00:26:44]So, now we're going to talk about how we screen for these chromosome conditions during pregnancy.

[00:26:53]So, that is done. It is very routine these days, but it has only been around for I don't know, like since 2000 10, 2008, something like that. So, honestly, a lot of you listening to this like maybe your parents did not have this when they were pregnant with you. I know I didn't. Um but it's very standard now.

[00:27:20]So, it is something called non-invasive prenatal testing or NIPT, also called cell-free DNA sequencing or screening. Cell-free DNA screening.

[00:27:34]And how this works is that this is a pregnant woman, of course.

[00:27:40]Um And this is her bloodstream.

[00:27:44]And her bloodstream is obviously going to contain her DNA. So, that's shown in the blue.

[00:27:53]Then we have mom's DNA, but it also contains DNA from the baby.

[00:28:00]And so, how that occurs is that when your cells die, which they're doing all the time. Like it's not a bad thing.

[00:28:08]Your cells die and reproduce all the time.

[00:28:11]They release your DNA into your bloodstream.

[00:28:15]That also happens for the cells of the baby's placenta.

[00:28:21]So, the placental cells are also dying and they are also releasing DNA into the mother's bloodstream.

[00:28:30]So, when we take the mother's blood, it contains some of the baby's DNA and that's how we do this screening.

[00:28:40]And so, that sample is used to then estimate essentially the proportion of the number of certain chromosomes.

[00:28:53]So, typically, this test just looks at the 13th, 18th, and 21st chromosome.

[00:29:00]21st being looking for Down syndrome. Um are other common chromosome conditions.

[00:29:09]And then it will also look at the sex chromosomes, the X and Y.

[00:29:14]So, it will determine the baby's sex as well as if the baby may have a sex chromosome condition.

[00:29:23]So, those are the ones that it is looking for.

[00:29:26]However, it is still a screening.

[00:29:29]It is still screening these chromosomes because it's not looking directly at the baby's DNA. It's taking it from mom.

[00:29:39]Um It is also possible. I'm not going to go too far into this in this video, but it is possible for the DNA of the placenta to not match the DNA of the baby.

[00:29:53]Kind of complicated, but because this test is looking at the placenta, it's not uncommon for it to flag a condition, but that condition is present in the placenta, but it's not actually in the baby.

[00:30:10]So, that plays into like the chance for a false positive.

[00:30:15]Um but because it's a screening, it doesn't give you a yes, baby has this, or no, baby does not. It tells you high risk or low risk.

[00:30:27]So, at the top here is an example of a low-risk NIPT.

[00:30:35]So, this determined baby was a male, so X and Y chromosome.

[00:30:40]The fetal fraction was 8.3%.

[00:30:44]That means that in the mother's blood, 8.3% of the DNA was from the baby. So, that has to be a high enough percentage for them to actually do this test.

[00:30:58]And it came back low risk for all of these conditions.

[00:31:03]Trisomy 21, 18, 13, monosomy X, or Turner syndrome. I'm not going to really go into that, but and then triploidy.

[00:31:13]Triploidy is when the body has three of every single chromosome.

[00:31:20]So, not just three of the 21st, but three of every chromosome.

[00:31:27]Um that is another condition that is not compatible with life, I guess. Um you can't you can't live with triploidy, but this screens for that as well.

[00:31:40]And so, it tells you that now the risk is less than one in 10,000. So, we can't say it's zero, but we can say that it's significantly reduced.

[00:31:53]The bottom is a high-risk test. So, again, a male.

[00:32:00]Again, 8.3% fetal fraction.

[00:32:04]And it came back low risk for 18, 13, monosomy X, and triploidy, but high risk for trisomy 21.

[00:32:14]And yet, again, it's not going to tell you that the baby has it, that it's 100%, but it's telling you now that there's a 95 out of 100 chance that the baby has it.

[00:32:29]So, that's that's the test there. And then, if you want to know for sure, so this screens, it looks for potential chance for these conditions, but to know for sure, you have to do um amniocentesis or a chorionic villus sampling, um which are more invasive procedures that actually take a sample of the placenta or the amniotic fluid to be able to tell for sure um if the baby has it, but that's NIPT, that's NIPT results.

[00:33:06]This is a big part of prenatal genetic counseling is counseling people on NIPT results.

[00:33:13]Um yeah.

[00:33:16]Something else that can happen is low fetal fraction. So, sometimes the report will come back and it will fail because there wasn't enough fetal DNA in the sample.

[00:33:30]So, that's another thing we counsel on because sometimes it can mean that the placenta is too small, um which can be associated with chromosome conditions and other things.

[00:33:43]So, we kind of talk to people about that, but it can also occur if the mom is on blood thinners, has like autoimmune conditions, or is severely overweight, um it can reduce the amount of fetal DNA that's in the sample. So, that's just a possibility.

[00:34:06]But now, we're going to go further into that like 95 out of 100 and less than one in 10,000 chance. So, what those are are the PPV and NPV, or positive predictive value and negative predictive value of the test.

[00:34:29]So, we'll talk about what that means.

[00:34:31]The positive predictive value is the chance that a positive result is a true positive result. So, that's that.

[00:34:43]It was a screen positive.

[00:34:46]The PPV is 95 out of 100. So, the chance that that is a true positive result.

[00:34:55]And then, the NPV is the opposite, the less than one in 10,000.

[00:35:00]So, we'll talk about how that is calculated and how it can depend on the maternal age and like the baseline risk for someone to have a chromosome abnormality.

[00:35:16]Okay.

[00:35:17]So, for this test, we'll say that we're talking about this NIPT screening.

[00:35:23]It has a sensitivity of 95%.

[00:35:27]Sensitivity is the chance that a positive result will be picked up.

[00:35:34]So, if the baby has Down syndrome, the chance that the test will tell you that the baby has Down syndrome is the sensitivity.

[00:35:44]So, there's a 95% chance.

[00:35:46]Specificity is the opposite, the chance that a negative result will return negative.

[00:35:53]If the baby doesn't have it, the chance that it will be negative.

[00:35:58]Okay.

[00:35:59]So, in this scenario, we have a 38-year-old patient.

[00:36:05]For a 38-year-old patient, there is a one in 100 chance of Down syndrome.

[00:36:12]One in 100.

[00:36:14]So, if we fill out this table, we're going to say that there are 10,000 total people.

[00:36:22]10,000 total 38-year-old patients.

[00:36:25]Out of that, there will be 100 that have Down syndrome.

[00:36:31]And 9,900 that do not. So, that's that one in 100.

[00:36:37]100 with it, 9,900 without.

[00:36:41]Now, these are our screening results.

[00:36:45]So, NIPT coming back positive or negative.

[00:36:49]If we have a 95% sensitivity, then if there are 100 people with true Down syndrome, 95 will come back with a screen positive, and five will come back with a screen negative.

[00:37:07]Same over here, 99% specificity, means that out of the people that do not have Down syndrome, 9,801 will correctly screen negative, and 99 will incorrectly screen positive, even though they don't actually have it.

[00:37:30]So, that's the false negative and the false Wait, false negative and false positive rate.

[00:37:38]So, calculating the PPV would be the number of true positive results.

[00:37:47]So, these people have it and they screened positive. True positive results divided by the true positives and the false positives.

[00:38:00]Because it's the chance that if we get a positive, that it's actually going to be a positive, which is calculated by true positives over all positives. So, these are all of our positives.

[00:38:18]These are our true positives.

[00:38:20]And what we get there is 49%.

[00:38:25]So, that means that with this test, with this sensitivity and specificity, if you're a 38-year-old patient and you test positive, there's a 49% chance that it is actually a positive, that the baby actually has Down syndrome.

[00:38:45]Okay.

[00:38:47]Um and then, NPV is greater than 99%.

[00:38:51]That's usually the case, usually what you look at, but the chance that a negative result is actually a negative.

[00:38:59]What's interesting is down here, we're looking at a 28-year-old patient, where the risk of Down syndrome is one in 500, rather than one in 100.

[00:39:13]So, here, out of 10,000 people, only 20 will have Down syndrome.

[00:39:19]So, that changes these numbers. We're only going to get one false negative, 100 false positives, and that makes our PPV 16%.

[00:39:34]Much lower.

[00:39:36]So, exact same test, exact same result, but just depending on the mother's age and therefore the background risk of Down syndrome is going to change how likely it is that that result is actually positive.

[00:39:58]So, this always confuses me cuz I'm like, how could the same result be like more concerning in one person and less concerning in another?

[00:40:10]Um the thing that really helped me understand this is the fact that we are more so expecting Down syndrome in someone who's 40 years old.

[00:40:27]And so if we get a positive result, we're going to be like, yeah, checks out, makes sense, like that we kind of expected that.

[00:40:35]Whereas in a 20-year-old patient and we get a positive result, we're going to be like, that's suspicious. Like, I'm less less worried about that, so I'm not really thinking that's correct.

[00:40:49]And the analogy for this that I like is if I told you it is going to rain today in Seattle, you'd probably be like, yeah, checks out, cool, like I believe you, I'm expecting rain.

[00:41:06]If I told you that it's going to rain today in the Sahara Desert, you'd be like, uh I'll believe it when I see it. Like, I don't think that's actually going to happen.

[00:41:17]So, exact same forecast for rain, but just depending on how likely that actually is is going to determine how likely we are to believe that result is like the way that I kind of learned it and I think that that helps a lot, so that's NIPT and screening for chromosome conditions.

[00:41:44]And now with the rest of our time, we are going to talk about carrier screening and some recessive conditions.

[00:41:52]So, these are not at all related to maternal age, they're just things that happen um due to our genetics and we can actually get tested for um prior to having a baby to determine our risks of these things happening.

[00:42:10]So, kind of as you saw with the meiosis and chromosomes, um we get two copies of every chromosome and therefore two copies of every gene in our body, one from mom and one from dad.

[00:42:26]And when we're talking about recessive conditions, that means that to have the condition, you have to inherit a mutation on the gene from mom and a mutation on the gene from dad. So, you have to have two mutations in the same gene to have the condition.

[00:42:49]And so, this is showing where both parents are carriers for a particular condition. So, meaning that they have one working copy of the gene and one mutated copy of the gene.

[00:43:06]So, they do not have the condition because they don't have both mutated copies, but they are carriers of a mutation.

[00:43:16]And so, this on the top is showing one parent, so we'll say mom, she's got her working copy and her non-working copy.

[00:43:27]And then this is dad with his working copy and non-working copy.

[00:43:32]And with every child they have, there's a 50% chance of each parent passing on the working or the non-working copy.

[00:43:43]So, their four possibilities are that both parents will pass on their working copy, that one parent will pass on a working copy and one parent will pass on a non-working copy.

[00:43:59]So, that makes up two possibilities because either parent could pass on that copy.

[00:44:06]And then a 25% chance that both parents pass on the mutation or the non-working copy and you get a child with whatever that condition is.

[00:44:19]So, that's just the basics of carrier screening. Um there are like hundreds and hundreds and hundreds of recessive conditions that we could screen for.

[00:44:32]Um most of the time people are screened for like three of them or 14 of them, but you can be screened for like 830 conditions, so there's a lot of stuff that can go wrong when you have a baby.

[00:44:49]Um but that's like the basics of carrier screening, so one condition that a lot of people have heard of is cystic fibrosis. That's one of the most common recessive conditions um that you can be a carrier for.

[00:45:06]Um so, one thing that is very common in prenatal genetic counseling is you don't actually know the carrier status for mom and dad. It's very common for OBGYNs to order carrier screening for a pregnant mother and we'll get results back. We'll see, oh, she's a carrier for cystic fibrosis, but we don't know if dad is a carrier or not because he's not part of the prenatal care. He's not being treated by the OB, so they're not ordering carrier screening for him.

[00:45:47]I don't agree with this process at all.

[00:45:49]I would have to say, I hate this process because it makes people so unnecessarily scared when it's honestly unlikely that their partner is also a carrier and unlikely that there's even any chance that the baby's going to have a condition. So, like if one parent is not a carrier, you can't get this outcome. You can't both pass on the mutation, so it's nothing to worry about. So, this is something that I would see very commonly is like the mom found to be a carrier for cystic fibrosis, let's say. So, let's say mom is pregnant, she found out that she's a carrier and we're counseling the couple on what to do next.

[00:46:37]So, what you have to know is the carrier frequency for the father. So, like how likely it is that he is a carrier, which for most conditions is dependent on ethnicity. Different conditions have different carrier frequencies across different ethnicities.

[00:47:00]Um and so, if I'm seeing this patient who tested positive as a carrier, I would probably ask what ancestry her partner has.

[00:47:12]If he is Caucasian or white, there's a one in 25 chance that he is a carrier.

[00:47:19]So, that means we know mom is a carrier, one in 25 chance that dad looks like this.

[00:47:29]25% chance that if they are both carriers, the baby will be affected. So, 25% * 1 in 25 gives us a one in 100 risk that the baby is affected with cystic fibrosis.

[00:47:45]So, that's what I would quote to mom as like that's how concerned we are that the baby has cystic fibrosis is one in 100, but we would have to test dad to know for sure.

[00:47:57]And then um in African-Americans, the carrier frequency is one in 60, so that's a one in 240 risk to the baby and one in 95 for people of Asian ancestry, so one in 380 risk.

[00:48:13]Um and this is different for every condition, so it gets really fun when I've got a patient who came back as a carrier for three or four things and we're trying to spell out all of the risks, all of the potential chances for her baby to have something.

[00:48:33]Um so, that's like basics of carrier screening.

[00:48:36]Now, I'm going to talk through a few complicated conditions. These are a few that I saw a lot in carrier screening and they are ones that function a little bit differently in terms of the genetics to um like cystic fibrosis is very simple, two copies of the gene, you need two copies to have the disease.

[00:49:00]Um these are a little bit more complicated.

[00:49:03]So, the first one is called alpha thalassemia.

[00:49:09]Alpha thalassemia is a blood condition.

[00:49:12]Um so, our hemoglobin, the component of your blood, is made up of alpha globin subunits and beta globin subunits.

[00:49:24]Um coded for by the HBA genes, so hemoglobin alpha, and HBB genes, hemoglobin beta.

[00:49:35]And depending on mutations in those genes, you can get different blood conditions.

[00:49:41]So, this condition we're talking about mutations of the alpha globin genes or HBA.

[00:49:50]Unlike cystic fibrosis and most recessive conditions, we do not have just two copies of hemoglobin alpha, we have four.

[00:50:02]So, you get two copies HBA1 and HBA2 from one parent, and then HBA1 and HBA2 from your other parent. So, you have four total copies.

[00:50:18]So, this is a normal result having normal working HBA1s and HBA2s.

[00:50:27]This is what you got from one parent, and this is what you got from the other parent. That's normal.

[00:50:33]Now, because there are four, there are a lot of different possibilities for mutations in these genes.

[00:50:44]For these, it's typically a deletion.

[00:50:46]So, like a full deletion of the gene and not just like a mutation. So, that's why I just colored them in red.

[00:50:55]So, the first possibility is that you have one mutation. So, from one parent, you got a mutation in one of the alpha globin genes, but you have the other one working normally, and you have both from the other parent working normally.

[00:51:13]So, one out of four are mutated. That's called being a silent carrier.

[00:51:19]You are a carrier because you have a mutation, but you don't have any symptoms, any issues. Um It's there's just the possibility that you could pass that on.

[00:51:33]Second possibility is that we have two mutations.

[00:51:38]This can either occur on the same chromosome.

[00:51:43]So, where you got both mutations from the same parent, or on different chromosomes. So, you got different a mutation from one parent and a mutation from the other parent.

[00:51:57]These are both considered alpha thalassemia trait.

[00:52:02]It's not alpha thalassemia. It is you're still a carrier. Um these people might have like mild anemia that shows up on blood work, but it's not a condition.

[00:52:16]It's not a serious condition at all.

[00:52:19]Doesn't have any symptoms or require any treatment.

[00:52:23]And it's the same regardless of if they're on different copies or the same copy.

[00:52:31]The main thing here is it matters for inheritance.

[00:52:35]So, for having children, these are very different results, and we'll talk about that with the next sheet of paper.

[00:52:44]Um and then having three mutations and one working copy is called HBH disease.

[00:52:52]That's like the classic alpha thalassemia.

[00:52:56]Um it leads to severe anemia, oftentimes like enlargement of the spleen and liver, um jaundice, requires blood transfusions.

[00:53:08]So, that's like the classic disease.

[00:53:12]And then if you have all four mutations, that's called HB Barts or hydrops fetalis, and that is typically fatal. Um typically that results in like a miscarriage or a stillbirth, um because it leads to hydrops, which is like a buildup of fluid in the whole body, um in a fetus, and it's not associated with good outcomes, but it's because of having such severe anemia.

[00:53:48]So, those are the different possibilities with these four genes.

[00:53:52]Now, we'll talk about the inheritance.

[00:53:56]So, it was really common that I would get couple a couple where both of them were silent carriers. So, both of them have that one mutation, and then three working copies.

[00:54:14]And that sounds really scary. It sounds scary that you're both carriers because you think, okay, there's a 25% chance the baby will have alpha thalassemia, but that is not true.

[00:54:28]Um so, this is our Punnett square again.

[00:54:32]So, like this is mom and this is dad.

[00:54:35]Mom has two working copies on one chromosome, and then one mutation, one working copy on the other, and dad has the same.

[00:54:46]So, there's a 25% chance that baby will be perfectly normal, no mutations.

[00:54:53]50% chance that one parent will pass on their mutation, and the other will pass on the two working copies. So, 50% chance of baby being a silent carrier, just like the parents.

[00:55:09]And then a 25% chance that they both pass on their mutation.

[00:55:16]However, that's just alpha thalassemia trait. No symptoms, no treatment needed, no concerns.

[00:55:27]So, I would often talk to couples that were both carriers, and they were super concerned, but it was like the worst thing that can happen is your baby has two mutations, and has no symptoms.

[00:55:40]Like it's going to be okay.

[00:55:42]Um where the issue comes in. So, down here, we have one person with alpha thalassemia trait. So, one mutation on one chromosome, one mutation on the other chromosome.

[00:55:58]This other person also has alpha thalassemia trait.

[00:56:03]Also no symptoms, but both of their mutations are on the same chromosome.

[00:56:10]So, these parents have the two different options for that middle category, the two different alpha thalassemia trait.

[00:56:23]What happens here?

[00:56:25]There's a 25% chance of being a silent carrier.

[00:56:29]There's Oh, no. 50% chance of being a silent carrier. So, um this parent passing on two working copies, and the only thing this parent has to pass on is one mutation, one working copy, so they're always going to pass that on.

[00:56:46]50% chance of silent carrier.

[00:56:49]Here, because this person has both mutations on the same copy, 50% chance they're going to pass that on. 50% chance we're going to end up with HBH disease.

[00:57:05]So, that is much more severe, and you can see how the type of alpha thalassemia trait matters. If this parent looked just like this parent, all of their children would look like this. They would all just have alpha thalassemia trait.

[00:57:27]But because they have the two on the same copy, there's a risk of HBH disease.

[00:57:34]Um and I just wrote carrier frequency is this is very common in Asian ancestry.

[00:57:41]So, a one in 20 um carrier frequency, especially of looking like this. This is very common in Southeast Asian ancestry.

[00:57:53]Um whereas Caucasian people, less than one in 500 risk of being a carrier. So, significantly, significantly different um when we're talking about ancestry. And ignore this random black box. I started writing silent carrier on accident when it's HBH disease, and I drew a black box over it because I was already so deep in this um piece of paper that I could not go back and do it all again. So, yeah.

[00:58:30]Maybe I need to buy white out.

[00:58:33]Okay.

[00:58:35]So, now, I was going to talk about beta globinopathy, beta thalassemia, but I think I'm just going to skip um and do my last piece of paper because this has already been a pretty long video.

[00:58:50]Um and the last one we're going to talk about is fragile X syndrome.

[00:58:57]This one is completely different.

[00:59:01]Fragile X syndrome is associated with intellectual disability and um autism, sometimes seizures, and like different facial features, but mostly intellectual disability.

[00:59:18]Um and it is caused by the FMR1 gene, which is located on the X chromosome.

[00:59:29]So, most of the conditions that we've talked about and vast majority of conditions on carrier screening are on those first through 22nd chromosomes. So, the autosomes that everybody, male and female, is supposed to have two copies of.

[00:59:48]The FMR1 gene is located on the X chromosome.

[00:59:53]Females have two X chromosomes and males have an X and a Y chromosome.

[00:59:59]I always give the disclaimer, I'm talking about typical genetic sex. I'm not talking about how you identify. I'm not taking into account sex chromosome conditions. I'm talking about typical genetic sex.

[01:00:16]Females have XX, males have XY.

[01:00:19]And so, males have only one copy of the FMR1 gene. Females have two copies of the FMR1 gene.

[01:00:28]And so, in this scenario, if a female has a mutation on one of her FMR1 copies, she also has a working FMR1 copy.

[01:00:43]And so, she's going to be less severely affected than a male who has a mutation on his one and only FMR1 copy. If that makes sense. So, typically, this affects boys more severely than it affects girls.

[01:01:02]Um but, the type of mutation is a little bit unique. So, most of the time we're talking about the change of a DNA letter. So, like a C becoming a G, a G becoming a T.

[01:01:17]Uh fragile X is called a repeat expansion disorder. So, there is a section of the fragile X FMR1 gene that has these repeats of the letters the CGG, CGG, CGG, CGG, CGG repeated over and over again.

[01:01:37]Um and depending on how many of those repeats you have, that determines how well that gene can function, um how the protein can be made.

[01:01:50]And so, normal, not mutated, no fragile X, is having between 5 and 44 repeats. So, if you have If you're a female and you have 20 repeats on one of your copies and 32 repeats on your other copy, that's normal. That's fine.

[01:02:11]Um everything functions normally.

[01:02:14]Intermediate is 45 to 54 repeats. This is also fine.

[01:02:22]You don't have fragile X syndrome.

[01:02:24]But, what happens is as the number of repeats increases, there is a higher chance of it expanding from one generation to the next.

[01:02:37]So, essentially, when there are so many repeats, the body's DNA replication kind of gets confused.

[01:02:47]And so, it can actually slip and cause more repeats. So, if a mom has 50 repeats, maybe her child will now have 70 repeats. So, it expands from one generation to the next. And that's why we flag people with an intermediate result because they shouldn't have a child with fragile X. It shouldn't expand this much.

[01:03:17]But, it could expand to this range, which could then expand to this range in the children's children. So, we're talking about inheritance.

[01:03:29]The premutation range is between 55 and 200.

[01:03:34]In this range, you do not have fragile X syndrome, but you could have a child with fragile X syndrome. So, it could expand to this full range.

[01:03:46]Um of over 200 is where you actually have fragile X.

[01:03:52]And like I said, if a female has over 200 on one of her copies, she's going to be less severely affected than a male that has over 200 on his only copy.

[01:04:05]Um one reason we do talk about premutations is these people do not have fragile X, but they do have a risk of premature ovarian insufficiency in females.

[01:04:20]Um so, typically, menopause before like 40 years old. Um the ovaries stop working.

[01:04:29]As well as something called fragile X associated tremor ataxia syndrome.

[01:04:35]This is something that occurs like after the age of 50 and um presents with tremors, trouble walking, cognitive changes. Um and that can be associated with having a premutation.

[01:04:53]So, that's one thing.

[01:04:54]If someone has an intermediate allele, there's a chance they could have a child with a premutation who could be at risk for these things. Someone with a premutation is at risk for these things and has a chance of having a child with full fragile X. So, I know this is complicated.

[01:05:15]Um and this bottom part just shows the inheritance.

[01:05:21]So, if dad is typical, no mutation on his one X chromosome, and mom has a typical X and one with a premutation, so one in that premutation range, when they have children, there is a 50% chance of her passing on this X or this X with each child.

[01:05:47]Dad is going to pass on his X to any girls and his Y to any boys.

[01:05:53]So, there's a 25% chance of having a daughter who's completely unaffected that gets this X and that X.

[01:06:01]25% of having a son that gets mom's normal X and dad's Y. So, typical.

[01:06:09]25% chance of having a daughter that gets mom's mutated X. So, now she has a normal one and a mutated one like mom.

[01:06:21]This may be a premutation, so in that same range, or it could expand to the full mutation range, in which case she would have fragile X.

[01:06:35]Um there's really no way to know unless we do genetic testing.

[01:06:41]And then, um 25% chance of the son getting that mutated, which could stay a premutation or could become a full mutation.

[01:06:52]And like I said, the son would likely be more affected than the daughter if they had the same repeat range.

[01:07:02]But, yeah.

[01:07:03]That is fragile X syndrome.

[01:07:05]Um I have been talking for so long, so I'm exhausted. And I think I'm going to take a break now. Um but, I was going to do the beta hemoglobinopathies. Maybe I'll do that in a future video.

[01:07:21]Um but, I hope that you enjoyed this prenatal genetics video. That was a lot of information to cover.

[01:07:29]I hope you enjoyed. Um let me know if you learned something, if you want me to talk about any other like prenatal things, but I hope that that was interesting and I will see you guys next time.

[01:07:43]So, sleep well, everybody, and good night. Good night. Good night.