Genetic Conditions PDF

So hopefully what we're seeing with this block is finishing up kind of our background on regulation to start really doing that thing I promised of here's the phenotype, here's the disorder, here are the genes involved. And so everything that we're going to be doing moving forward will be taking some...

So hopefully what we're seeing with this block is finishing up kind of our background on regulation to start really doing that thing I promised of here's the phenotype, here's the disorder, here are the genes involved. And so everything that we're going to be doing moving forward will be taking something we've either talked about in some context, you've had in another class, and specifically saying here's the gene that caused that and here's why. You ready? So much of our goals for this section is categorization. I don't want you to simply memorize this gene goes with this condition with this outcome. I want you to start to see themes. The skeletal muscular system will be affected in this way because these genes are important in that system for that activity. We'll have cardiac anomalies because we are affecting cardiac development. I want us to begin to take classes of genes, types of genes and start categorizing them. And so we start that with the neuro and structural. This is actually probably one of the most important areas of genetics from the perspective of the brain is the most sensitive compartment to change. A lot of our malformations or congenital anomalies also impact the brain. Anything that affects development has the potential to impact cognitive development. So if it's a structural condition, it can theoretically impact the brain. And for some odd reason, we see the brain constantly, I shouldn't say for some odd reason, there's a completely logical and justifiable reason, the brain gets impacted because it is so sensitive to change. Now, impact is a wide spectrum, right? We have complete cognitive impairment versus developmental delay. We have a wide range of phenotypes when we talk about anything that is subjective. Does that make sense? So when it comes to the brain, neurological outcomes are often secondary to other things. And so we'll see things like metabolic channelopathies. So we're losing specific signaling channels. Gene regulation issues can impact the development of the neurological compartment. And then of course, disorders that are associated with sequence repeats. Where we've actually lengthened or shortened genetic material, causing an impact in the development of those cells and specifically the maturation of critical cells. And then of course we can have peripheral neuropathies. As with any compartment, not all mutations even in the same gene are created equal. There is a wide difference between complete loss of function and mild or reduced function. If I completely eliminate the activity of a gene, delete it, it's just gone. That is going to have a vastly different impact than if I can still get low levels of expression. And so we can use our lac operon as an example of this. If I actually lack the genes for lactose permease, I can never sense lactose in my environment. But if I have the gene and it's just got a lower level of functionality, I'm still gonna be able to have some of that sensing and thus a different impact. Does that make sense? When it comes to anything congenital, we just literally mean present since birth. Something that we observe from the onset. When you have a complex system like humans, complex genetic interactions are expected. And so some genes can mitigate the effect of a pathogenic variation while others can further complicate it. And so when we're looking at some of this, we can't always just pay attention to one gene. We need to really look at are also other things affected? Are there environmental or lifestyle considerations as well? So we use those genome-wide association studies to analyze any groups because many, many, many genetic conditions are one key word, rare. They are not common. If they were, we'd have a better sense of them like some of our cancer understanding. Many of these are so rare in fact, they affect maybe one in 100,000 families. Not just one in 100,000 people, but families. And so we have an incredibly low level of presentation. The only way that we can study something like that is to pool data from multiple places. I found a case in this country. Here's a case over in that country. How does that relate to other conditions with similar phenotypes? Can we use that information to identify what the actual pathogenic variation is? Sequencing is still somewhat expensive. It's becoming much closer to standard of care, but only in specific arenas. So I imagine that many of you have not gone to your personal physician, your primary care physician, and gotten sequenced. Right, you didn't do that on Tuesday? And so until that reality becomes possible for everyone, much of what we're doing is based on that comparative. Can we find something similar? Can we find something close? And how can we classify and group things? So while we have identified many, we still have a lot to learn, and it's only through these genome-wide association studies, these pooling of massive data sets that we can actually get to the bottom of a lot of things that we're seeing. Does that make sense? A lot of this study is all about what's the most likely culprit? What is the probability that if you inherit this change, you're gonna see this phenotype? And how do we take that information and help patients with it? So when it comes to neurologic, it's our most difficult, because almost all of them are polygenic and complex. Huntington's feels really straightforward, right? Because you've heard about it. You inherit the change, you've got the condition. But there are spectrums of outcomes there. If you are a homozygous dominant individual, your risks are substantially higher than if you're the heterozygous individual. Absolutely vastly different outcomes if your changes are longer than shorter. So let's start with one of our more complex, which has a bit of a sordid history, because there was some falsified data in the science. Always fun when people make up their data. So Alzheimer's, this is considered the most common neurodegenerative disorder. What does that mean, neurodegenerative? Means that you're expecting a decline from previous abilities. There was an established baseline, and we're seeing less activity compared to that baseline. It is considered to be strongly influenced by genetics. And there are many studies that have shown significant autosomal dominant inheritance patterns for this condition. The complications of that are, of course, some of the things that we have come to learn are more closely correlated with more complex changes and interactions. But we have been able to find very strong correlations for some of the early onset forms. So my big caveat to this is there is much we do not understand about Alzheimer's disease, including for me how to pronounce it. We don't understand a lot of what this condition does because it's actually very difficult to study. And in terms of our familial histories, we can get a better picture, but there is information out there that complicates the picture. So we are gonna focus on those ones that we know are strongly correlated. And they're strongly correlated with the rare early onsets, those worst case scenarios on the spectrum. And those include the amyloid beta precursor protein, or APP, pre-sentilin I and II. This is all about amyloid beta processing. It's all about trying to identify a marker for degenerative plaque development. And so it's based on that formation of amyloid plaques. When it comes to another factor that we can point to for this, we are looking at APOE. And APOE is associated with that same autosomal dominant inheritance form, and it can actually work alongside those other three to worsen the prognosis. And so rather than being a marker of this is the definite, you get this, you have the condition, it's helpful in line with the other alterations. And so this is where we get to have a fun. Pathogenic variation is what we're talking about here. All of these genes have normal function, normal expectations for expression, and the pathogenic variation is going to be changing it in some way. Some of them are gain of function, some of them are loss of function, but ultimately changes in these four have known associated increased risks for Alzheimer's development. When it comes to this particular variant, this is considered a polygenic form, and it's very specifically correlated with also having those increased cardiovascular risks that are also seen with some of these patients. The APOE Epsilon-4 variant. All right, so from this slide, we are not spending a bunch of time figuring out what each of these are doing, right? What we're trying to do instead is say, okay, this appears to be correlated with a known phenotype of Alzheimer's because it appears to be present for the development of those plaques that we know we can see in patients. So that's the extent of our connection there because these are unclear risks. These are really associated with those rare early onset forms. Other risk factors for Alzheimer's become much more complex. The reason we start here is because you're talking about condition with so many unknowns. And so it really shows us when we make the determination, this is correlated. It's because there's strong evidence that when you have pathogenic variation in this, your risk of developing the disorder is significantly increased. There are no percentages to that. There's no, I have this, so I have a 30% chance of getting Alzheimer's because it's just not that clear yet. Does that make sense? So let's go on to another one that has a little bit more clear of a pattern. And so ignoring the other, the pictures on the right which are just showing you family pedigrees, this is a rare disorder. Again, we're in a neurogenic disorder and it's characterized by what is called DID mode, which is diabetes, diabetes mellitus, optic atrophy. So we've got that connection with diabetes and optic nerve, right? And deafness. So we are affecting significant blood flow here and significant maintenance of blood glucose, right? What compartment is that? It's our liver, right? So what we are looking at is actually an ER transmembrane glycoprotein being known as WFS1, Wolfram Syndrome 1. That is what's being shown here. So now let's spend some time with the pedigree. You will see some phenotypes written there. Although it does appear to be affecting every generation, what seems to be, why would this seem more recessive than dominant? So you have to look here, mild loss, more significant phenotype here, and then two children with more significant phenotypes. So it's sometimes where our clear cut, yes, no, starts to bleed when we have this spectrum of presentation. So even though our first question of is every generation affected, we now have to kind of modify with to what degree? Are there additional factors? But don't worry, your questions and examples will be more clear cut than that. So looking at this, we can actually see dominant inheritance from this condition as well because we can have that spectrum of phenotype and because it's going to have different disease manifestation. You are a dominant pathogenic variant when you create things like haploinsufficiency, when you create a toxic product that your system can't deal with. And so just having one of those mutations is enough to create the toxin, if you will, for lack of better phrasing. Does this make sense? Okay, the one you're actually familiar with. In terms of this, remember we focused on its autosomal dominant inheritance and this is all about expansion of a trinucleotide repeat. The greater the expansion, the worse the phenotype. You must achieve a minimum of 36 repeats before you will manifest any symptoms to be considered to have the full disease. This range here, 27 to 35, is not necessarily a problem for the person, but is absolutely a problem for the next generation where further expansion can occur. So tying this back to things that we know about chromosomes, how do we get the expansion? Slippage, misalignment, rearrangement, chromosomal level or replication level. Structural variation of this chromosome leads to this condition, specifically, HDT gene. So if we look over here, we can see just a general concept of inheritance. We know it's inherited dominantly, but having the homozygous dominant is far worse than if you do still have some function. It's correlated with an earlier age of onset, younger and more severe phenotype. The more expansions you get, same thing. The more expanded, earlier age of onset, more significant phenotype. Make sense? So that's our clear distinct gene to neurological only. Now we get to do structural with overlap. Major structural anomalies, congenital anomalies, structural anomalies due to genetic mutation are always to say the same thing. We have altered the expected phenotype of a body part due to a change in genetics. Whether that's expression, availability, pathogenic, variant in terms of creating a missense, any of the things we talked about as potential variation in block three can cause these. As a result, not all changes are created equal. A deletion in one base is different than a deletion in 20 bases from the same gene. Splice variant that forms one shape is different than a splice variant that forms a different product. The type of pathogenic variant you have can play a role in what your outcome is, and thus we get a spectrum. But they're still the same disease or the same disorder because the same gene was affected or even the same family of genes, depends. So some of our examples of congenital anomalies that affect the neurological compartment include our open neural tube defects, which we hinted at before and you've definitely had in another class. So you're about to see some lovely callback slides coming up here in a second. But specifically spina bifida, which we know to be our most avoidable due to simple lifestyle changes, right? How do we help prevent, it is considered to be completely preventable in many cases, spina bifida. Folic acid during pregnancy, during development, right? So other choices that we have are things like syndactyly and our congenital myopathies. So do we remember the anatomy callback? Yeah, I'm not going through these, these are for you. To remind you of what we're talking about when we talk open neural tube defects. So let's talk about spina bifida from the genetics perspective. Homeless sustained folate metabolism enzymes, including our reductase, our synthases, our coenzones, all the numbers of this pathway can contribute. But our main culprit here, the MTHFR, our reductase, that's going to be a direct correlation between the satiated risk. And the reason we have this error is because of our lack of folic acid in this process. When you have an actual pathogenic variation in this, it is no longer preventable with diet. Does that make sense? If you have a pathogenic variant in this, you are going to affect actual movement of cells, you're going to affect migration, you're going to affect polarity, you are going to prevent your ability to actually close that neural tube. Does that make sense? So this is not a list that I expect you to know, I just want you to see. You're talking about a pathway. When you're talking about a biochemical process affecting any step in that can lead to a similar phenotypic outcome. The place at which you induce the effect can correlate with the severity. MTHFR pathogenic variants have a significant direct correlation with open neural tube defects, MTHFR. So other anatomy callbacks, we're all on the same page. What are we doing here? We got our limb bud, we're making our limbs. And so now we're going to talk about syndactyly. Where are we predominantly dealing? Hands and feet, right? Much of the consequences of syndactyly are the result of either inappropriate or lack of apoptosis, or inability to form critical early structures like the notch at the ectodermal ridge, the apical one. So, not really what I care about, right? The part that I care about is what genes are doing this. And so in this case, we're actually looking at multiple genes because this is a complicated thing, making a limb. We touched on the idea of the balance between promoting growth and promoting apoptosis to give us that lovely separation. And so loss of either of those things can create the problem here. And so you can see we have our simple versus complex and complicated forms of the syndrome. And then how they're defined is based on the underlying architecture in those fusions. Is it a lack of space between versus actual fusion of bone? Versus additional material that should not be there making this surgical repair more complicated, hence complex. Does this make sense? When we have these things, I care more about what's going on in the genes. And so one of our key genes here is the HoxD13 or 13. This gene plays a role in both our syndromic and non-syndromic syndactylase, meaning syndromic implying multiple systems are involved, multiple changes are observed, versus non-syndromic only observe the syndacty, right? The syndrome implies multiple systemic alterations. That's what that word is meant to imply. And it's going to follow our autosomal dominant inheritance because it's gonna have incomplete penetrance. We are going to find that we are affecting the ability to actually generate the structures from a very early point. And so we can see our HoxD, genes are playing a very early role in this, hence we can see everything downstream of that role being affected. Sorry, if this was covered, I apologize. Did I just turn myself off? Okay, so did I just turn my sound off? That would be bad. And so this is another one. Please do not memorize these pictures. That's not the goal here. I want us to link HoxD genes to this process. And so it's all about patterning and playing a role in actually deciding what cells become what. That's a very early stage. And so that's how come you can end up with fingers that are fused or additional digits that shouldn't be there. Does that make sense? So let's move on to our congenital myopathies. This is, now we're in muscle. And we have five subgroups, yeah. I have a question about the previous slide. What is causing the male to female ratio to be nearly two to one? So there's a lot of factors that come into play, but there does appear to be a hormonal issue in terms of that. Like there's, males seem to be the presence of or lack of the extra X chromosome that changed the wide, that seems to be playing a role. To be honest, not to be honest, it's only transparent. I am not as familiar with the complex interactions of the Hox genes in those early developments, but I do know that in terms of a hormonal conversation, there can be differences between males in utero and females in utero. One of the more interesting ones is of course, the impacts that male offspring produce in mom, including changes to the brain that differ compared to female offspring, which is always fascinating. But again, some of that is harder to study. So in terms of the male ratio, it appears to be hormonally driven. So congenital myopathies in our last three minutes, we are looking at predominantly five categories, but you'll notice I put a little star by one of them because we're really not gonna talk about the congenital fiber type. We're gonna focus on core, anemolines, centronuclear, and myosin storage. And essentially all of these to identify require biopsy of the muscle. I cannot identify this particular thing without that. I had a guest for like two seconds and then they went right. So in this case, even changes in the same gene can have different patterns of inheritance. So what is really defining the pattern of inheritance is losing or gaining one copy sufficient to cause the condition. If losing or gaining one of the two copies, it's gonna be dominant. If it is a loss of function mutation and I lose the function of one copy and I see the phenotype, then I have a haploinsufficiency. I need both copies to produce enough product. If gaining, if the pathogenic variant causes a gain of some sort, gain of material, gain of product, gain of a particular activity like an increase in apoptosis, an increase in cell growth or proliferation, some sort of increase, and it only takes one extra to do that, then that is also gonna be inherited dominantly. Does that make sense? So our example of that would be HTT expansions. So this is where we're at. Do we remember this from MPP? And we will pick up right here with differentiating and categorizing. Sound good? So Wednesday will be another one of those days where we flow into our next packet. Questions or concerns in our last minute because I am determined to stop on time today. Okay, so then I will finish up with one comment, which is yes, right now it feels condition, gene, inheritance pattern. So one of the things that we're going to do is make sure that we're spending time creating those categories. I will not ask you to differentiate between genes that cause the same impact, like HoxD3 from another Hox. That's not the goal. I want you to be able to identify a Hox change as having a specific implication in limb development. Does that make sense? Okay. Thank you so much.