NEONATAL Genetics: What you NEED to know at the BEDSIDE!!!

Let's imagine you own a car manufacturing plant. So basically, you own a factory that produces cars. And in your factory, you produce every single tiny part of that car. I don't know if that's true in car factories, they probably outsource the glass and the carpets or whatever. But in your special factory, you make every single part of the car. Now, every single one of those pieces of the car needs instructions for how it needs to be made. So for example, let's say the door handle. In every computer in the factory, there are going to be different sets of instructions for how that door handle is made. So maybe one set of instructions or code on the angle of the metal. Maybe another set of instructions on how it attaches to the electrical system. Maybe another set of instructions on the color of the handle. So all these codes are in your computer system, but then how does the car actually get made? Well, now let's imagine that the instructions or the code on the computer then get printed out on the floor. And workers from the floor go pick up the instructions and then go gather up the pieces so that they can assemble the car handle. This is exactly what's happening in the cell. The DNA is the code, the instructions for what needs to be made. When it gets printed out, it becomes the mRNA. The mRNA can be read by the ribosomes, who are the workers. And in the ribosomes, the mRNA can then be converted into proteins. So the ribosomes are using the code in the mRNA to actually build the proteins or the part of the car. The collection and arrangement of proteins in our bodies is basically what makes us who we are. And DNA is basically the code for all the proteins that are made and how those proteins are arranged, which is why DNA is the code to all our lives. Hi, I'm Dr. Tala, and I've been a neonatologist for 17 years now. And we deal with a lot of genetic stuff in the NICU. So our lovely members of this channel asked us to talk about genetic issues. If you're interested in having that sort of power to request which videos that we want to watch, then please consider joining our membership. So that's what we're going to talk about today. One, what are genes and chromosomes? And two, how can things go wrong? In the next video, we'll talk about the various genetic tests that we use in the NICU. So make sure that you catch that one when it comes out. Let's get back to the car parts. In all, there are 20,000 individual codes. That doesn't mean that there are 20,000 different parts of the car, because like we said, even with the door handle, there were several different codes that were responsible for making various parts of the door handle. Same thing in our bodies. You'd think that there would be millions of genes that code for proteins. But in reality, there are only about 20,000 protein coding genes in our bodies. In our body, the gene, so that's the fragment of the DNA that actually codes for a protein. The code or the gene in our body actually looks very much like a code in a computer for something else entirely. In that, the DNA code is made up of a series of letters which actually all represent nucleotide bases. I'm not going to go into a lot more details about nucleotides, but you should understand that nucleotides are the building blocks of DNA. There are four different types of nucleotides, and we will represent each one by a letter. T-thymine, C-cytosine, A-adenine, and G-guanine. No reason to remember that, but just kind of think C-T-A-G. The code, the DNA code, is just a bunch of those letters representing those nucleotides. You could have C-T-A-G, G-G, C-T-U. Endless, endless amounts of those letters are what's making the DNA. Now, the computer prints out the mRNA. So that is the RNA that gets transported to the ribosome where the worker can actually look at the instructions. When the mRNA is made, one of the letters is changed slightly. We don't have to go into that detail. But basically, the worker or the ribosome looks at the order of those letters and can make whatever they need to make out of that. In the cell, each three letters in a row represents one amino acid. So depending on which three letters the code was originally given, a different amino acid is made by the ribosome. So for example, if the initial code on the DNA was C-T-G, then the ribosome knows it has to make leucine. So we're going from the DNA code to an actual amino acid. A protein, remember, is made out of lots of amino acids. Remember, amino acids are the building blocks for protein. So depending on how big the protein is, if you go back and look at the gene that's actually coding for that protein, then obviously the gene is going to be longer. So for example, hemoglobin alpha, which, as you all know, is a protein in red blood cells, has 141 amino acids that make up the protein. So if you go back and look at the gene, you will see 141 of the triplet nucleotide code that each one of those will then give the code for each 141 amino acid. I just want to stop here for a second so that we can all just acknowledge how absolutely incredible this is that this code even exists. I mean, this would make, like, blow out the World War II coding movies out of the water. Like, this is so insanely intelligent. The different nucleotide bases, each three actually code for a different amino acid. The fact that that even exists and the fact that somebody, some geniuses, were able to figure out this whole code, it really is unbelievable. Okay, let's get back to DNA and a few more things that you need to know about DNA. One, all of our DNA, so all that code, is packaged into 46 chromosomes. So think of the chromosomes as just as files on your computer. Those 20,000 codes, and remember, we said that there are 20,000 genes that code for proteins. So those 20,000 codes are on files on the computer. So a total of 46 chromosomes. So you open one of the files and you'll have some of the instructions for how to make different bits of the car. What's interesting, though, is that where that information is stored on the file is pretty random. So it's not like you open one file and it has all the codes that are needed for the engine. Not at all. You could open one file and there's a little bit of code on how to make the steering wheel and some code on the lower part of the handle and a code on the transmitter. I don't really know car parts, but they're really all over the place. And that is the same with the chromosomes in the body. Because if you think about it, it's just a set of proteins that are pretty much going into every system and organ in the body. Two, the DNA in each chromosome is actually just one really long continuous strand. So if you look at it, you might not immediately be able to tell which of those three letters are actually part of an amino acid and which of those three letters are just kind of like filler in there. So going back to the computer in the car factory, just imagine that in each file, you've got loads of ongoing code and the computer or somebody has to realize where the actual code that produces the part is buried in there. And that's the same thing in these long streams of DNA, these long strands of DNA. The bits of the DNA that actually code for the protein, so the genes are embedded throughout the chromosome. In that long strand of DNA, the areas of the DNA that actually code for the proteins are called exomes. Remember that word, it will come up later. The rest of the DNA that doesn't actually code for anything, but it's lots of those nucleotide bases are called introns. So we used to think that introns were just like junk DNA. So they're not really doing anything, they're just kind of separating the different genes. But in reality, as more and more is being discovered, really, those introns are also involved with upregulating, so deciding how quickly the proteins are going to be made from the actual genes, as well as they're involved in like repair and everything else of the genetic material. So obviously the introns are important too, but those bits of DNA are not coding for proteins. What's really fascinating in that really long strand of DNA in each chromosome, only about one to two percent of the DNA actually codes for proteins. So only one to two percent of the DNA are considered exomes. The rest of the DNA are considered introns. So the majority of DNA is what we used to think of as junk DNA. Obviously it isn't. We're not going to have 98% junk DNA. Three, you have the same genetic material, the same DNA in the same chromosomes, pretty much in every single cell in your body. There are some exceptions to this, like there always are in medicine, but I'm not going to go over that now. And for the most part, you cannot change that DNA. You cannot change your genes. Again, we're going to talk about this a little bit in the next video, how there have been some new advances with changing genes in babies with inborn errors of metabolism. We'll cover that next time. But generally for the purpose of this, understand that you cannot change the genes in every cell in your body. This is really difficult for parents to understand when their baby has a genetic issue. Why can't we just fix it? Well, because it's literally in every cell in the body. A friend of mine who is also a neonatologist, Dr. Abby, explains it to parents as if they are making a cake and too much salt was put into the cake. So even if you know there's too much salt in there, after the cake is made, you can't go back in and actually remove the salt. I feel like that works well in explaining to parents why it cannot be changed. Four. Genes are inherited from our parents. Okay, this is where everything goes off from the car manufacturing plant analogy. Obviously, somebody in the car manufacturing plant just types out the code for the part. Whereas we all inherit our genes, our DNA from our parents. So our parents each have 46 chromosomes. As our father is making the sperm and the mother is making the egg, the chromosomes will divide into two and we will end up getting randomly 23 chromosomes from our father and 23 chromosomes from our mother. They will combine in the egg and we'll end up with the 46 chromosomes. So in reality, we actually have two copies of every single gene, mostly, again, exception. So we mostly have two copies of every gene. And what we consider coming from each parent as part of that gene is called an allele. So two alleles will make up the gene. You get one allele from mommy and one allele from daddy. Now, what's interesting when you think about the disease processes is sometimes if just the mother's gene works into making a protein, a functional protein, then that will be enough not to have a disease. So even if daddy's gene is not working or it works and it makes a weird protein, then still, if the mother's is functioning, then that's enough to make sure that we don't have the disease. For example, an autosomal recessive disease like cystic fibrosis. If we just have one functioning gene that makes a normal protein, then the baby will not have cystic fibrosis. Whereas there are other diseases where even if there's just one abnormal gene and one abnormal protein being made, then we're going to have the disease. So those are the autosomal dominant diseases. Things like tuberous sclerosis or achondroplasia. So with just one abnormal gene that makes an abnormal protein, we will end up with that disease. And the last general thing I want to say about genes is that you need to realize that it's not like one gene generally will determine one final outcome. Yes, there are some diseases like that. But generally, there is a lot of variability in just about every single structure in our body. And that is because many, many genes contribute to the final outcome. For example, it's estimated that about 160 genes, all found on different chromosomes, will contribute to our eye color. So it's not like one gene from the mommy makes it blue, one gene from the daddy makes it blue. And so 100%, the baby's eyes are blue. No, there are lots and lots of genes involved with even something as simple as the final eye color. So the genes are involved in many different systems at many different levels. Two, right now, let's talk about how things can go wrong. As you can imagine, with that huge long strand of DNA, there can be so many little things that can happen. Just like if you're thinking about a long series of letters, how many different ways that that could go wrong. Genetic abnormalities are a huge problem in the NICU, where it's estimated that about 20% of deaths are secondary to genetic issues in the NICU. In fact, just the general prevalence of genetic disorders in the NICU is estimated to be pretty high. Based on just newborn screen results, it's estimated that about one in 500 people has a genetic abnormality. But if you think about it, those are just the ones that are being tested for the newborn screen. Other studies have estimated that between 10% and 20% of all NICU babies will have a genetic abnormality. Let's talk about some of the common genetic abnormalities that can happen, like what's actually happening at the genetic basis. So the first one, which is kind of very logical to think of, is called an SNV, or a single nucleotide variant. You can probably guess what's happening here, but basically, in the long code of DNA, one of those nucleotides that's in a gene, that's in an exome, so within an area of the DNA that's coding for a protein, one of those nucleotides gets switched out for another nucleotide. So instead of an A, there's a T in there, or whatever. So why is that a problem? Because what we already said is that just changing out one of the nucleotides of those three will change the code. So if you change out one of the nucleotides, then the collection of those three nucleotides could now be coding for a completely different amino acid. An example of this type of mutation is sickle cell disease, where you literally have one nucleotide that's being changed, which makes a new amino acid, which then makes a new protein. So instead of making the correct hemoglobin, you end up with hemoglobin S, which is the hemoglobin that's a lot more likely to sickle. So that is really just from one change in the nucleotide, which most of the time is inherited. Realize in this case that it just takes normal genes from one parent to not make that hemoglobin S. So basically, as you all realize, sickle cell disease is an autosomal recessive. With just one normally functioning gene and protein, there will be enough normal hemoglobin where the patient doesn't have the severe symptoms of sickle cell disease. But sickle cell disease is an SNV type of disease. B, insertions or deletions. So this is where either the DNA is being replicated or bits of damaged DNA are being repaired. And accidentally, extra bits of DNA get put in or some extra bits of DNA get removed. A few extra bits of DNA could be completely irrelevant. For example, if we've got a whole bunch of new letters within the introns that aren't actually coding any proteins, then we probably don't have to worry about it as much. But if you have extra DNA within an actual gene that's coding for a protein, then it might add extra amino acids. So it would make the protein very abnormal. Or if some of the gene got removed, then obviously we're going to be missing some of the necessary amino acids and proteins that need to be made. And this could result in bad genetic outcomes. An example of a deletion type of genetic issue is DeGeorge syndrome. And that is also called 22q11.2 deletion syndrome. So just like what it sounds like, you're missing a whole chunk of the bottom of chromosome 22. And it's estimated to be about 3 megabases. So about 3 million bases of those nucleotide bases. So TA whatever, times a million. And patients with DeGeorge syndrome can have really bad outcomes. So they can have developmental delays, cardiac defects, hypercalcemia, and immune issues. So also realize that even though we're just missing a small part of chromosome 22, the proteins are obviously affecting the formation of lots of different types and parts of the body. So that's why there are so many different symptoms involved, not just with the heart or whatever. I'm going to do a really quick aside here because I do want you to understand what P and Q means because it comes up a lot in the genetic testing. So I'm just going to do a quick aside here. Realize that most of the time in the nucleus, the DNA is all just like one really big strand. It kind of all looks like a large tangled necklace. It's only when the cell is getting ready to divide that all the chromosomes, like kind of line up and they're like in their nice package chromatids and chromosomes the way that we're used to seeing them like in science lab or whatever. So you have the 23 pairs of the chromosomes all lined up in metaphase if anybody's getting tested on that anytime soon. So for each chromosome, each chromatid, so these are like the two arms on each of the sides are attached by a centromere. The short part of the chromosome, so the upper part is called P and the lower part is called Q. So for example, if you read that there is a 1P deletion, then that means that there is a deletion on the short arm of chromosome 1. So DeGeorge syndrome basically means that there's a deletion on the long arm on the bottom part of chromosome 22. C, copy number variants. So in the previous one that we talked about with sickle cell, we talked about a single nucleotide variant. So just one letter was replaced by another nitrogenous base, so another letter. In this case, this is copy number variants. So this is where three letters or something that may or may not code for amino acid can be repeated over and over again. Again, this can happen during replication as well as during repair. Just like every genetic variation, this might not mean anything. The repeats may be in an intron, so we're not coding for them anyway. Or maybe the three repeated letters don't even code for amino acid. So it might really not affect anybody from a clinical standpoint. However, there are some diseases that are considered triplet repeats. So you have a repeat of those three nucleotides over and over and over again. And the more you have of them, the higher the chance that you are of having the actual disease. And there are many diseases like this, for example, Fragile X disease, which obviously is involved with intellectual disabilities in males. There's Frederick's ataxia, Huntington's, myotonic dystrophy is another one that we see in the NICU. And you can actually see how many triplet repeats of these there are in the DNA. And the higher the number of the triplet repeats, the more severe the diseases and the earlier that the disease will present. D, structural changes like inversions or what we call translocations. This is a really important concept to understand from like an inheritance standpoint. So, for example, let's say a mother is completely clinically normal. She has all her DNA and is coding for all the proteins that her body needs to function normally. But if you go and actually look at the DNA, what you might end up finding is that even though she has all the DNA she needs, the DNA is not packaged into the chromosomes as it should be. So, for example, a small piece of chromosome 21 might be packaged onto chromosome 14 and vice versa. So for her, she has all the DNA that she needs. But the problem with this is when her DNA goes to divide and she's making eggs, then she might end up making eggs with either too much DNA or too little DNA. So if she has extra bits of chromosome 21 in one of her eggs, then and that egg ends up being fertilized, then that baby is going to end up having three copies of chromosome 21 or Down syndrome. So again, translocations are very important if the mother is having babies, because obviously if she has a translocation, even if it's balanced and a balanced translocation means that she has all the DNA that she needs, she's making all the proteins that she needs to make. She's still at increased risk of having a baby with an unbalanced translocation and a chromosomal abnormalities. So this is where a baby has a whole extra chromosome or lacks a whole chromosome. A lot of the time, this mistake happens when the egg is dividing. And instead of getting one copy, which it should have of each chromosome, there's two. So, for example, if the egg has two copies of chromosome 21 and then it meets the father's one copy, then they'll end up with having three copies of chromosome 21 or they'll end up having trisomy 21 or Down syndrome. Theoretically, this can happen with any chromosome, but the ones most likely to happen with are chromosomes 13, 18 and 21, which is why we see those trisomies in the NICU sometimes. It can happen with other chromosomes, but generally, the longer the chromosome, the more genes it carries, the less likely the baby is going to survive pregnancy, the more likely that it will be an early miscarriage or something if it's a trisomy chromosome number one. OK, if you reach this far, then please like this video. And I do also just want to say there are other things that can go wrong with genes, but the ones I covered today were the important ones for you to understand in the NICU when we think about which genetic testing to do. So make sure you go and watch the next video on genetic testing now. If you're interested in neonatal education, then please subscribe to our channel. Again, thank you so much for being here.