Genetic Testing in Epilepsy: Understanding Results and their Impact on Care - Webinar

Welcome everyone to today's webinar. I'm Laura  Lubbers and I'm the Chief Scientific Officer for CURE Epilepsy and I'm delighted to have you join  us today to learn more about epilepsy genetics. Since our founding in 1998, CURE Epilepsy has  raised millions of dollars to fund epilepsy research that supports our mission, which is  to find the cure for epilepsy by promoting and funding patient-focused research. Cure  Epilepsy provides grants that support novel research projects that advance the se

arch  for cures and more effective treatments. In this second webinar of our 2024 CURE Epilepsy  webinar series, we will be talking about epilepsy genetics. The webinar is entitled Genetic Testing  and Epilepsy, Understanding Results and Their Impact on Care. This is the first of two webinars  this month that address CURE Epilepsy's ongoing focus on epilepsy genetics. Genetic testing  actually has increased our understanding of the causes of epilepsy exponentially in the past  two decades, speci

fically helping researchers understand the many genes responsible for  rare childhood epilepsies. In addition to ending the often way too long diagnostic  odyssey for patients and their loved ones, genetic testing can help enable tailored treatment  options and family planning decisions. However, there are still many individuals who lack a  genetic diagnosis, including adults who may not even be aware that they could benefit  from genetic testing. In this webinar, attendees will learn about who

may want to discuss  genetic testing with their doctor and prepare them to ask key questions after genetic testing has  been completed. Today's webinars, like all of our webinars, is being recorded for later viewing on  the CURE Epilepsy website. You can also download transcripts of all of our webinars for reading. This webinar is being presented by Katie Angione, who is a neurology genetic counselor at  Children's Hospital Colorado in Aurora, Colorado. She provides genetic counseling for a dive

rse  population of patients with complex neurological disorders with a focus on developmental and  epileptic encephalopathies. Her primary goal as a genetic counselor is to support patients and their  families through education, advocacy and research efforts focused on understanding the natural  history of these conditions and eventually working towards precision diagnoses and treatments. Before  Katie begins, I'd like to encourage everyone to ask questions. We'll address the questions during  t

he Q and A portion of the webinar. Please keep in mind you can submit your questions anytime  during the presentation by typing them into the Q and A tab located on your WebEx panel and click  send. We'll do our very best to get through as many of the questions as we can. We do want this  webinar to be as interactive and informative as possible. However, to respect everyone's privacy,  we ask that you make your questions general and not specific to a loved one's epilepsy. So  with that, I'll tur

n it over to Katie. Thank you so much, Laura. Thanks for the  introduction and thank you to CURE Epilepsy for the invitation to do this webinar. And thanks  to all of you for joining. So hopefully this is informative and we have plenty of time at the  end for questions. So please, like Laura said, put your questions in the chat and we'll have  time for discussion at the end. So as Laura said, I am a genetic counselor at Children's Hospital  Colorado in Colorado, and I'm going to be talking today

about some basics of genetic testing. So we're going to talk a little bit about just some genetic testing terms and how to read a  genetic testing report. I think sometimes genetics can be like another language, so it's helpful  to just understand what all of those terms mean, everything that you're looking at when you're  trying to decode that very complex report. We'll discuss some different types of genetic  changes, the difference between different types of variants, so benign, pathogenic a

nd uncertain  variants. And then explore a little bit about what to do once you've received a genetic diagnosis  or even an uncertain diagnosis and talk about how those results can potentially impact treatment  or management of disease moving forward. This is an image we share all the time in  just explaining the basics of genetics. So we all have our bodies that are made up  of cells. Our DNA is stored in chromosomes, so that's the X shaped figure on the picture. So  chromosomes are comprised o

f large continuous DNA molecules all very tightly wound up and packaged.  And those chromosomes contain genes. So genes are just a segment of DNA that encodes a protein  product. So something that gives our body an instruction for how to build something that it  needs to grow, develop, and function properly. Those proteins are complex compounds that are  composed of hundreds or thousands of amino acids. So those are the units that make up the proteins. So this is an analogy I use a lot. So genes

and proteins are like recipes and the final  product. So the gene is like that recipe. It's the instructions that tell your body how to  make a protein that your body needs to function. The protein itself can have a lot of different  important roles in the body. So it can provide structure and support, it can transport materials  from one place to another or send signals, protect the body from things like viruses and bacteria and  carry out all the complex chemical reactions that we need to kee

p our bodies going. Like I said,  those proteins are made up of smaller units called amino acids. There are 20 different types and the  sequence of those amino acids is what determines the proteins 3D structure and what their specific  function is and how they might interact with other proteins in the body. So the genes are like the  recipe, the protein is like the final product, that cake in the picture, and the amino  acids are kind of all of those ingredients that go to make up that final pro

duct. A genetic variant is any alteration in that DNA sequence that is different from what's seen in  the majority of people. There's no perfect genetic sequence. We all have differences, although  everyone here today we share about 99.9% of our genetic information. So there is very little  left that is different from one person to another, but those differences are what make us all look  different, make our bodies function differently, and they're also what can lead to genetic  diseases. So a v

ariant which we sometimes refer to as mutations when they're pathogenic  or disease causing variants. A variant can be benign. So meaning that it doesn't cause  any problems, it's just a normal variation within our DNA sequence. It can be pathogenic,  meaning that it does cause some sort of disease or problem. Or it might be uncertain, which  just means it's different from what we see in the majority of people, but we don't know  enough about that specific change to know for sure whether or not

it causes any problems. So I'm going to go really quickly through this, but we can always come back if there is specific  questions. So there are a lot of different types of pathogenic variants or mutations that  we can see, and this is something that is typically indicated on a genetic testing  report. So we can see missense mutations, which is a way to describe kind of a typo.  So it's a change in one DNA based pair or one letter in that code for a different letter.  And that is what causes th

e substitution of one amino acid for another within the protein. So  it's a change of one little unit of that protein. A silent mutation is something where the DNA code  changes, but that final product actually doesn't. So if you think about the recipe analogy, it's  like if there's a really minor typo on a recipe, you're still going to understand what it means.  It's not going to alter that final product. A nonsense mutation is a change that signals  the cell to stop building the protein too ea

rly. So that causes a shortened version of that  protein also called an early truncation. So this, in a lot of cases, can be very severe  because there is a big portion of that gene that's missing. Depending on where  that change happens within the DNA sequence, we can sometimes see differences in how severely  impacted somebody is. There's also insertions, deletions or duplications where there might be  just a few letters or even much larger pieces of DNA that are added or deleted or duplicated

. So  there's things that can alter the number of pieces in that DNA sequence. And because the DNA has a  very specific way that it is read, that can alter what's called the reading frame of the gene. So  that's called a frameshift mutation and that often eventually results in an early truncation. So the  DNA can only be read three letters at a time. It's very specific. So you can imagine if you insert  two letters or you take away four, it's going to throw off that three at a time reading frame

. But this is an example of what a missense mutation looks when you're talking about that three to  time reading frame. So you can see the sentence the cat ate the rat, if you change just one  letter in that sentence, you end up with the cat ate the bat. So it changes the meaning,  it changes the final outcome of what's going on just with one letter being different. And  then you might also have a different type of missense mutation where instead of the cat ate the  bat, you're changing it to th

e car ate the rat, which is a much bigger change. It doesn't make  any sense, whereas the last one made a little bit of sense. So depending on where that mutation  is located, you can see more or less impact. So this is an example of a silent mutation.  Sometimes if there's a particular letter that is changed, it doesn't impact that final  product too much. So I think in this case we have the letter C just becoming lower case  and that doesn't change the final outcome of the sentence. A nonsense

mutation, so this  is we're talking about an early truncation, so where that sentence or that DNA code stop  short, and you can see here if that letter A is taken away or changed and the rest of the sentence  isn't there, we don't know what happens, we're just left with the cat. And then insertions, so  these next few slides we can go through quickly, but insertions, deletions, duplications, all  of these are adding or taking away letters that either they might not shift that reading frame. So

here we have the bat cat ate the rat, which definitely changes things but it still makes  sense and it doesn't alter that sentence going forward because that's an in-frame insertion. So  it's not messing up that three at a time reading frame. Other times we might add, we might  see additions or duplications that do alter that reading frame and that create a sentence  that doesn't make any sense anymore. So if you can click through a few times. There we go. All right, so just a quick way to illus

trate those different types of mutations. The other  thing that you'll always see included on a genetic testing report is the inheritance  pattern for that particular disorder, that particular gene. So there are a few of  mean inheritance patterns that we tend to see. Autosomal dominant in which a mutation in just one  copy of the gene. Each copy of the gene is called an allele. We have two copies or two alleles for  each gene. So for autosomal dominant conditions, a mutation in just one allele

is sufficient to  cause disease. These types of mutations can be inherited from a parent who is also affected  by the condition or they might be brand new in the patient. For a lot of rare disease we  see that there are autosomal dominant changes, but they are brand new in that child, so they're  not something that was necessarily passed down. And that's something that we talk about a lot  is the difference between saying that a disorder is genetic and saying that it's inherited. So genetic does

not imply inherited. Not every genetic disorder is passed down from a parent. We  can see a few things called reduced penetrance, incomplete expressivity and mosaicism. These  are all things that can alter how a genetic change is expressed. So reduced penetrance means  that someone might have a mutation that has the potential to cause disease, but it might not  cause as severe disease in each person who has it because maybe it's being influenced by other  things. We also see incomplete expressi

vity, which is very similar, but that just means that  not every single person who has a disease causing or potentially disease causing change has  any symptoms at all. And this is where we can sometimes see a mutation being passed down from a  parent who doesn't have any apparent symptoms of that condition so they did not know that they're  at risk to have an affected child. We can also see mosaicism, which just means that not all the cells  of the body have the exact same genetic makeup. So th

ere might be a portion of cells that have  a damaging mutation and a portion of cells that don't. And depending on what particular tissues  or what parts of the body are important in that condition, we can see someone being affected more  severely or less severely. In autosomal recessive conditions, someone must have a mutation on both  alleles or both copies of the gene in order to cause disease. So in most cases, when we see  a child with an autosomal recessive condition, typically each parent

is what's called a carrier  for that condition. Carriers don't have any symptoms of recessive diseases because they have a  second copy of that gene that's working just fine and that is enough to not have that disease.  But if two parents happen to be carriers, and we are all carriers for a few things and we don't  usually know what they are unless we specifically get carrier testing or have a child born with a  recessive condition, if each parent passes that mutation down to a child, then we w

ould see a  child who's affected with a recessive disorder. We can also see X-linked conditions. So those  are disorders that are caused by a mutation on the X chromosome, which is one of the sex  chromosomes. So biological females typically have two X chromosomes and biological males  typically have an X and a Y. There are some variations that we can certainly see and a handful  of different genetic conditions that can be caused by differences in those chromosomes. So  for X-linked conditions,

we typically see that biological males and females are affected  differently. So we might see in some cases that the majority of patients with that condition are  female because it is a mutation that if it were present in a male who only has one copy of the X  chromosome that would be so severe that that fetus might not actually make it to birth. Or we might  see that males who are born with those conditions might be more severely impacted than females. And then sometimes we see conditions where

only males are affected because it only takes one  mutation to cause that disorder. And females who have two X chromosomes and have a copy of that  gene without a mutation do not actually express that condition. So again, there are some things  that can impact expression in X-linked disorders, the biggest one being skewed X in activation. I  know these are a lot of terms I'm throwing out there and not explaining in detail, but for the  sake of time, X in activation is basically just the process

where, in females, our cells turn  off one copy of the X chromosome in each cell so that we're not over expressing all of those genes  compared to males who only have one X chromosome. And if there is a genetic mutation on the X  chromosome, there are sometimes females who their body might just randomly turn off more  copies of the cell that have the mutation, which means that they would be left with more  normal copies or typical copies active. So they may be more mildly affected, whereas othe

rs might  have more of the normal or typical copies turned off in their cells and so then they're left  with a larger proportion with the mutation, so they may be more severe. Next slide please. So why is genetic testing important? There are definitely a lot of reasons. I'm going to try to  run through them pretty quickly here. But first of all, we are hoping when we do genetic testing  for an improved understanding of the diagnosis, so an understanding of why we're seeing the  symptoms we're se

eing. When we're able to make a genetic diagnosis, it might give us a  better understanding of the natural history of that condition, the disease course over time  so we can answer questions about what to expect as somebody gets older. In some cases it can  impact medical or surgical decision making. It might help us to select medications that  are known to be effective in that particular disorder. It tells us if there's any other things  we should be watching out for. So do there tend to be kid

ney problems in this particular disorder?  Should we be doing brain MRIs for any structural changes looking at the heart, things like  that. So just knowing if there's anything else we should be paying attention to. And then it can also help to correct any misunderstandings. So if there's concern that,  for example, something was caused by a traumatic childbirth or caused by something like that,  a genetic diagnosis can help to clear up some of those misunderstandings. It can help with  family p

lanning. So understanding if this is a brand new or if it is a condition that was passed  down from parents helps families to understand recurrence risks and if there's a chance of  having another affected child in a future pregnancy. The inheritance pattern tells us, like  we just talked about, whether this is recessive, dominant or X-linked condition, which  again helps us understand recurrence risks for both the parents of if we're doing  testing on child, for those parents and then for that

child once they get older, if they have  children of their own. It helps open the door for prenatal or even preconception testing options. We typically would refer to a prenatal counselor if this was something that a family was wanting  to discuss further and it could lead to earlier diagnosis and potential improved outcomes in  an affected child. Prenatal testing doesn't necessarily mean that you don't carry that  pregnancy to term, but it does mean that if you know that you are pregnant with a

child who  is affected with a genetic disease, you can start implementing different management things early  on which tends to lead to better outcomes. And it can also help to identify any at risk family  members or anyone else in the family who might be a carrier for the same condition. So it can help  them to make informed choices about their family planning. Anytime we make genetic diagnoses, we  are improving research, improving understanding of those conditions. So identifying more patient

s  helps to have better natural history studies, to have a better understanding of longitudinal  data, so how that disease looks over time. And eventually, and this is the direction we're  moving and very excited about, is exploring the efficacy of precision therapeutics. So ultimately  getting to drugs that might target specific genes, specific variants and help to improve outcomes  in patients with those disorders. Diagnosis can help to identify other families or other  similarly affected indi

viduals, which for a lot of people can be really helpful to just have  that community and be able to talk to other people who understand what that disorder looks like and  everything that's involved with it. And it opens the door for involvement in patient advocacy  groups, patient and family meetings. A lot of rare diseases are starting to have conferences  for their specific conditions. So that's another way that we can build that community. And then it  helps to access specific resources. So

sometimes having a genetic diagnosis can make it easier to  get therapies approved, to advocate for coverage of medical supplies or medications that might  be helpful for that particular diagnosis. And then it just helps to provide more money  for disease specific support and research, drug development, all of those things. So I want to walk through a couple of different genetic testing panels and the different elements  to focus on when you get one of these results back. So this is what things

tend to look like.  Obviously from one lab to another there'll be some differences, but every report is going to list the  name of the gene. So over here you can see this particular report is for STXBP1. It will list the  variant, and this first part where it says C.969 del, so C stands for coding. So that's the change  in the actual DNA code. 969 is the address. So it's the number, it's the 969th letter in that  DNA sequence that makes up that gene. And del means there is a deletion at this loc

ation. The  P after that stands for protein. So that is the corresponding change in the protein that happens  as a result of the change in the DNA code. So this one it says p.met324cysfs*8. So that's a  lot of mumbo jumbo when you're not familiar with what all these terms mean. So again, P stands for  protein, change in the protein. Met and cys are both abbreviations for different amino acids, so  different elements that make up those proteins. That 324, again, is the address of this change.  So

it's telling you that that position 324, there's usually a unit called met or methionine  and instead it's been changed to this different unit, abbreviated cys or cysteine. The frame  shifts or the fs means frame shift. So there is a resulting shift in that reading frame, that  three at a time reading frame that we talked about. And the asterisk eight means that eight  units later in that protein there is an early truncation so that gene stops being built and  we don't get the rest of that prot

ein product. Heterozygous just is describing whether a variant  is present on one are both alleles. So alleles is just the two different copies of the gene.  Heterozygous means that it's present on one allele. Homozygous would mean that it's present  on both. Inheritance pattern is something that's typically listed in that main part of the  report. And then the variant classification. So you might see most labs are not going to  report out benign and likely benign variants because they are thoug

ht to be normal, they're not  causing any problems. But on a report you might see pathogenic, so this is definitely a disease  causing change. You might see likely pathogenic, which means that the lab is pretty  confident that it's disease causing, but it's not quite 100%. And then you might  see uncertain significance. So a variant that we don't have enough information about to  definitively classify, but that potentially fits the symptoms for which that test is being sent. This is just an exam

ple of what that might look like at another lab. So again, you can see a lot  of those same components are present. It tells you the name of the gene, the inheritance pattern, the  change in the DNA code and in the protein. This one says de novo, you can see under this genotype  section. De novo means new in the patient, which means that this was a test that included  some parental samples. So the lab was able to tell that this is a brand new change in that patient  and not one that was inherite

d. It also tells you the type of change. So you can see a missense  change and, again, it says that it is classified as pathogenic or definitely disease causing. This is an example of whole exome sequencing, which again contains all of those same components  but also has this part on the top that talks about everything that exome sequencing looks at. So  did they find a causative change in a gene that's associated with the symptoms or the phenotype  that was reported? Were there any variants and

genes possibly associated with that phenotype? So  those would be what we might call candidate genes or other findings that might be relevant, but  we don't know enough to say for sure. Secondary findings are changes that the labs that do whole  exome sequencing can choose to look at, or not, depending on the patient and family's preference.  So those are genes that have to do with risk for mostly adult onset predispositions for things  like cancer, serious cardiac issues and other disorders th

at have medical implications if  you knew that you were at risk for them. And then this particular test also included  M-T-D-N-A, which is mitochondrial DNA. I'm not going to get too much into that today, but  that's just a separate chunk of DNA that we have that is only passed from others and that's  not included in standard genetic testing. It's something that needs to be looked  at separately. So this report also lists results of that testing. Next slide please. So this is an example of a rep

ort for another type of testing, a microarray. So the first  couple that we looked at were panels and then whole exome sequencing and this is a microarray.  So whereas panels and whole exome sequencing read through either all of the genetic material or  all of the genetic material that's relevant to a specific phenotype or a specific set  of symptoms, a microarray is like if you took a textbook and you're just making  sure all of the pages are there. So you're not reading every single thing. It

doesn't look  at tiny, tiny changes within individual genes, but it looks for larger extra missing pieces.  So this report is describing a copy number loss and a copy number gain that were found in  chromosome eight. So this first copy number change part is telling you the size of those  changes, the location within the chromosomes. Again, in this example they're both on chromosome  eight. The P, and the P that's there, sorry, I can't see because it keeps wanting me to gain  control of the slide

s. The P is just describing where on the chromosome this change is located  and then all those numbers at the end are, again, an address. So it's showing you exactly  where that deletion and duplication are within that chromosome. Regions of homozygosity is  describing if there are areas found where genetic content is the same on both copies of the  chromosome. So we expect when we have a child, that things get rearranged and combined and so  that we are a blend of our parents and sometimes ther

e are regions of the genetic material that  just end up not mixing quite as well or there might be shared ancestry that causes just more  similarity between the two copies of the genes. That's not an issue in and of itself, but it  can cause a higher risk for recessive conditions because basically if you had one mutation and  things are exactly the same, you're definitely going to have another mutation on that same  gene. So that's something that is often looked at during microarrays to see if t

here's any risk for  recessive conditions in those particular regions. And then down at the bottom there's going to be  a description of the change and what genes are involved that might be clinically relevant.  And a lot of labs will include references, so links to publications about that specific  gene or that specific disorder and they might include details on how a variant was classified,  whether it was found to be disease causing or if it's uncertain, they might include some of that  evide

nce as to how they came to that conclusion. So not every report is straightforward.  When we're doing these larger panels, we often will land on an uncertain result and  sometimes that uncertain results might involve a lot of different genes. So you can see here  there are variants of uncertain significance that have been identified in 10 different genes,  which is not the most common outcome, but it is something that we can see when we're looking  at a lot of genes at once. And particularly, an

d I always point this out to families in pretest  counseling before we're sending testing so that they know what to expect. We see this more often  in families who have any ethnic background aside from Caucasian. And that's because the databases  that labs are using to determine what's just normal variation and what's potentially disease  causing, historically have not done a good job at accounting for just normal variability  between people with different backgrounds. That is finally changing.

There's been a lot  of efforts more recently to diversify those databases more so that we're getting less and less  of results like this. Most of the time when we do get a result like this, doing parental testing  clears up the majority of that uncertainty, but it is an area of genetics that we're  still working on improving our understanding a little bit better. Next slide please. So I always use this meme when talking about variants because it is one of the most difficult  things that we do as

providers is when we get a test report back, we have this variant of  uncertain significance. What do we do with that information? A lot of families, they'll  see a variant and they'll say, oh my gosh, that sounds exactly like me or that sounds exactly  like my child. This must be the answer. But it's not always that straightforward. So when we do  get these uncertain variants, we might do family testing to get a better understanding of is this  change present in other people in the family who

maybe don't have the same symptoms or is it  tracking in the family with people who all do have the same presentation? We might assess, does  it fit really well with what we're seeing in this patient? So if there are other symptoms that  are always seen in that particular disorder, is that something we're seeing in our patient? And sometimes that might mean doing a more targeted exam or doing additional testing,  whether it's biochemical testing, imaging, things like that, to look for other comp

onents  of that condition. And then sometimes we just need to wait and give it time. We're  always learning more about our genes and about specific variants. So oftentimes a  variant of uncertain significance ends up being reclassified down the road and then we have a  better understanding of whether it's something we can ignore or if it's something that actually  is diagnostic for that patient. Next slide. And then what do you do when a test is just  completely negative? It's important to know

that a negative genetic test doesn't mean that there's no  underlying genetic diagnosis. It just means that maybe there's something there that we're not able  to identify at this point in time. So sometimes if a test is negative, there might be a more broad  or a more comprehensive test that we can move to as a next step. So moving to something like whole  exome or whole genome sequencing. If we've done the biggest and most comprehensive testing and we  still don't have an answer, again, we just

have to give things time. So typically if we do something  like whole exome sequencing and that's negative, we usually recommend waiting about two years and  then asking the lab to reanalyze that testing. Your genetic data doesn't change over time. Your  genetic information is going to be the same, but our ability to interpret it is always  getting better. So that's where reanalysis can come in. And when we don't have a  genetic diagnosis, we just continue with symptom-based management and go f

rom there. So when you do get a genetic diagnosis from testing, what comes next? So all of the things  on this list, or at least most of the things on this list are definitely individual and some of  them are not the right move for everybody. So I think it's always helpful to discuss when you  get that diagnosis back, have a good thorough discussion with your ordering provider about  any management or treatment recommendations that might be different because of that disorder.  That's not always

the case. A genetic diagnosis sometimes just gives us a reason why and does  not give us any specific management changes, but sometimes it does and sometimes that changes  over time. So definitely a good idea to check in with either the ordering provider or if there's  a specialist who they refer you to, to talk more about it just to talk about any changes to  your healthcare plan. Inform other members of your care team or your child's care team. Sometimes it can be really helpful for people in

other specialties, not just genetics, but all  the specialties that are involved with what that disorder causes. It can be helpful for them  to have that context and that background in managing those symptoms. If you are comfortable  with it, informing the school, any therapists, other caregivers, so whether it's family members,  babysitters, other people that are involved in that person's care, that can be really helpful  for them to have a better understanding of what's going on. When it comes

to school, it can help to  advocate for individual education plans or IEPs. It can help to advocate for one-on-one attention  during class. So having a genetic diagnosis can sometimes open a lot of doors to resources that  can be really helpful. Sometimes you might be able to identify specialty clinics or family meetings  or conferences that are specific to that diagnosis and that can be a really great place to learn more  and to help your providers have some backups. So there's a couple of spe

cialty clinics at  Children's Hospital that I'm involved in that we basically see children with very specific rare  diseases. We make recommendations that go back to their primary team so the primary team doesn't  have to feel like they need to be an expert on this super rare condition. They can get support  from people who've seen more children or more patients with that disorder. Again, as I mentioned  before, it can help to connect with other families or patient advocacy groups if and when th

at's  something that works for you. It's definitely not for everybody. There's a lot on the internet  as we all know. So I think we always recommend that families take the things that they're reading  online, on message boards, on online communities, with a grain of salt and we try to just point  people in the direction of good resources. For a lot of disorders, there might be ongoing  or upcoming research or clinical trials. So it's always good to ask about those things and  to check in about t

hose things regularly to make sure that you know about anything that you  or your child might qualify for. There's also clinicaltrials.gov, which is somewhere that you  can search for those things directly, but working with a provider who's able to be the in-between  can be really helpful in making sure you're in the loop about those sorts of things. And I'll  say that's another thing that family groups are really good for is informing people who are part  of that group about those sorts of oppo

rtunities. And then it's also helpful to consider any  implications that diagnosis might have for family planning. So again, whether it's you have  a child diagnosed with a rare disease and you're wanting to know if there's any chance of that  happening again in future pregnancies or if it's someone who might have biological children down  the road and wants to know their chance of passing that genetic change down, it can be helpful. Just some quick online resources. I'm not sure if these slides

will go out, but I know this  is recorded. So just a few things that I use all the time and pass on to families all  the time. GeneReviews is really in depth information about a lot of different genetic  disorders and then they include surveillance and management recommendations over time.  So that can be a helpful guideline on the type of providers you might need to see and how  regularly you might need to have certain testing done. MedlinePlus is a more paired down version  of GeneReviews. So

it is the basics and this is something I often recommend, if you have family  members or people that are involved that want to know what's going on, but they don't need to know  every detail, that's a good resource to turn to. Nord Rare Disease Database and Unique are both  kind of additional places where there's a lot of information about different genetic disorders. And also same, MedlinePlus has a lot of great resources for just learning more about  genetic concepts. So that's a good place t

o go if you're looking at any of these  reports and you want to know a little bit more about the terms that are used or some of  the terms that we briefly talked about today, that's a really great place to turn. Thank you so much, Katie, for all of that information. Loved all of the animations. Start  with the Q and A portion of this webinar. Just a reminder, if you want to ask your questions,  please submit them via the Q and A tab on your WebEx panel and click send. We're getting  some thank y

ous from the audience and we have some questions. One is, this person was  informed that the gene that's been identified for Doose Syndrome has been found but not  for JME. Is this the case, do you know? So I know that Doose Syndrome or EMAS has  a couple of different terms for it. It's something that we've been trying for years to  find the gene and there are definitely some genes that have been associated with it. There's  still multiple different genes that can cause that presentation. Doose

is a clinical presentation and  so there's not one gene, one clinical diagnosis, there is a little bit more complicated than  that. JME, I know that there are some gene associations. I'm not sure off the top of my head  what they are. There's so many genes at this point to keep track of. But again, I think there's a  lot of patients who have a JME presentation who we're not able to find a genetic cause for.  So that might mean there is a genetic cause, but we don't know the full list of genes th

at  could cause that type of presentation yet. Another question for you. What about roadblocks  to insurance paying for genetic testing? Do you have any recommendations for  families who face that issue? Yeah, that can be really tricky and my experience  has been that insurance providers are always changing their policies. I would say that if  you work with a provider who's comfortable with ordering genetic testing, they might be able  to go to bat for you a little bit. So we often will write le

tters of medical necessity. A lot of  our physicians will have peer-to-peer discussions with insurance companies to explain the reasoning  behind doing testing. But it might be helpful if you're seeing that testing as getting denied,  you might be able to request a copy of their policy and some, sorry, I'm losing my voice,  some insurance providers actually cover very limited genetic testing, so maybe single gene or  a very small panel or microarray. And then very extensive genetic testing, like

whole exome  sequencing, but they might not cover a lot of the panels that we typically send in between. So that's something we struggle with a lot is wanting to send something more targeted,  but then only having the option to send something really comprehensive like whole exome  sequencing. So I would say have that discussion with your provider that you're talking with about  genetic testing, about what those options are and if there's something that would make sense  to send that would fit w

ithin that insurance provider's policy. There's also some genetic  testing labs that have pretty good self-pay options and patient assistance programs. So  some of the labs that we work with commonly, Gene DX and Invitae, Prevention Genetics, worked  with [inaudible 00:42:31] over time depends on the tests we're wanting to send, but a lot of those  commercial labs do have really good programs for self-pay options. So that's something else  to consider. I know sometimes going through a hospital s

ystem can lead to higher costs,  but going directly to the lab might be more feasible. So that's something to look into. I know that there have been some free testing programs. Is that still the  case for our community? Yes. So I work in neurology and with epilepsy, so  that's my bias here. Those are the things I'm most familiar with. But Invitae does have a program  called Behind the Seizure that is sponsored by a bunch of different pharmaceutical companies that  are working on or that have tre

atments for some of the genes on that panel. So that is an option for  children who have epilepsy that are under the age of eight would have access to that program. I know  Invitae also has a long list of other sponsored programs that is always changing over time, so I'm  not sure exactly what's on that list right now. And then Prevention Genetics definitely also has  some sponsored testing options as well. I would say that that's another thing that family groups  and patient advocacy groups are

good at informing their community about. So that might be a place  to turn if you're looking for a sponsored test that would work for you or for your child. Great, thank you. Here's a question. Would you recommend siblings get genetic testing? So it depends. So if there is say a diagnosis of a rare disease in a child and their siblings  are also children, so they're under the age of 18 and they're not expressing any symptoms of  that disease, we don't typically recommend what's called asymptoma

tic or predictive testing for  siblings until they're old enough to participate in that conversation. So that doesn't necessarily  mean 18. We definitely have those conversations with teens depending on exactly what the disorder  is and what their level of understanding is. But in general, we try to avoid testing minors unless  there is a specific treatment or something that could really impact the course of the disease. So  if a sibling, for example, is diagnosed with CLN2 disease, which is a g

enetic disorder that does  have a gene specific treatment, we might test a newborn sibling to see if they have that same  disorder because we know that it can be helpful to treat very early on and can see potentially  better outcomes when treatment is started earlier. So that would be the exception to that, is if  there are potential treatment implications. Thank you. Yeah, there's encouragement for  doing that if there's evidence to suggest that it would be helpful. If children develop  epileps

ies, but there's no known history for at least two generations, is there a  benefit for the parents to get tested? I do think it is still potentially beneficial  for parents to get tested. So if a diagnosis is made in a child and there's no family  history. It depends on the specific gene, but there are some disorders where someone  might actually carry a mutation but not have any apparent symptoms. So that could be helpful for  knowing about potential recurrence risks. I would say tuberous scle

rosis is a pretty decent example  of that. It has a very wide range of severity. So we sometimes see patients in clinic who have  that diagnosis, they have the genetic diagnosis, there's no apparent family history, but then we  test parents and one of the parents has the same change. So for things like that where there is  a wide range of presentation, I think it can be helpful if you want to know for sure. Here's a question relates to somebody's experience. This person had their son tested  and

turned out negative. It sounds like it was a panel with a handful indicating limitations.  Could you define the term limitations? So I think every genetic testing lab will  include this paragraph, sort of a disclaimer in the reports, about the limitations of current  genetic testing. And I think the biggest one at this point is just our understanding as a whole  scientific community of our genes. So we know we have about 20, 22,000 different genes within  our bodies, but at this point we only h

ave a good understanding of what about 8,000 of  them do. So there is a lot left that we still need to learn about. So that's the biggest  limitation in genetic testing at this point, is just our understanding. The other limitation,  depending on the type of testing, would be the technology. So not every single genetic test can  test for every single thing. Every test is looking for something different. So even whole exome  sequencing, which is meant to and understood to be very broad and very c

omprehensive, there are  certain types of genetic changes that whole exome sequencing or even next gen sequencing, which is  how most panels are done, is not able to detect. So there are things called trinucleotide repeat  disorders, which involve repeating sequences of the DNA code. That is something that requires  very specific testing. There are changes called methylation changes that are seen in disorders  like Prada Willie Syndrome and Angelman Syndrome, that requires very different specifi

c testing. So  I think that's why it's really important to try to work with a provider who has some understanding of  genetic testing if you can. I know that access can be an issue when it comes to genetic specialists,  but making sure that everything that is within the differential diagnosis has been tested  for with the testing that's been sent. Explain the difference between whole exome  sequencing and whole genome sequencing. So whole exome sequencing is looking at the  exome. So our genes a

re made up of exons and introns. So I think of this like a train. So  the exons are like the cars on the train that have most of the content of those genes and the  introns are these linking pieces in between that link that gene together. But when the body reads  it and makes it into a protein, those introns get cut out and the exons get put together into that  final product. So the exome is looking just at the exons, it's looking just at the train cars  and not at the parts in between. Historic

ally, we used to call those parts in between junk DNA,  which is a terrible term because we've learned over time that it is still very important. There's  a lot of components outside of the exons that help to regulate how genes are expressed, that help to  might work with gene and protein interactions. There's a lot in there, but we don't understand  everything that's in there quite as well as we understand what's in the exome. So the exome  is only about 2% of our genetic information, but we th

ink it makes up 90, 95% at least of  disease causing changes. So we've started doing whole genome sequencing to look at all that other  stuff, but we're still working on understanding what all that other stuff means and what it  does. So whole genome is more comprehensive. It's looking at more but, at least in my clinical  practice, we haven't seen a huge increase in yield between whole exome and whole genome sequencing.  So it is a direction we're starting to move. We're starting to send whole

genome sequencing more  and more often clinically, but we still have a ways to go and understanding of the other stuff  that's in that that's not included in exome. Genetics is so complicated, isn't  it? And there's still so much- It really is. Somebody asked a question, in the gene code in the report for some of the  transcripts, there was an NM in front of the information. Can you explain what NM means? So that's the name. That's just identifying the transcript that the lab is looking at. So f

or a  lot of our genes, there's kind of one DNA code, there's one sequence that the body's reading,  but it can take that and cut it up and put it back together in various ways. And there might  be multiple different transcripts or versions of that final protein that are important.  Sometimes there might be some that are more important in one part of the body and some that  are more important in others. That transcript is just the lab listing which version of that  gene that they're looking at a

nd how they're mapping that final change. It's based on that  transcript and not on a different transcript. I don't know if that answers your question. So complicated with all of those genes resolving into different kinds of proteins even from  similar sequence. That's really cool. I think you've already talked about this, but  if you could just answer it again, how often is it recommended to go back for an update or  re-analysis as new genes are discovered? I would say if you have done a lot of

genetic  testing and gotten uncertain or negative results, I would recommend trying to touch base with  either with the provider who coordinated the original testing or with a genetic specialist,  whether it's a geneticist or genetic counselor, every one to two years. That actual reanalysis,  once we get to the more complex testing, we recommend waiting two years in most cases,  unless there's a major change in symptoms or there's a decline of if things are progressing,  if there's a hospitaliz

ation, some of those things might trigger us to do things earlier just to be  like, we definitely want to make sure if there is any new information to find that we find it, but  we don't want to jump the gun on doing reanalysis because if we do testing today and we don't find  anything. If we do that same test again a month from now, the chances that we're going to find  anything new in a month's time are not very high. But the chances that we learn more over  two years, it's actually really dec

ent. Our understanding has improved a ton over the past  several years, and I think that will continue to kind of grow exponentially. So I think that's  a reasonable timeline. If there is a diagnosis, I would also recommend checking in every one to  two years for more information. There might be new research that's come out, new publications,  more patients that have been identified, and there might be research opportunities that  would be relevant. So I think that's a good timeline for checking

in, even if a diagnosis has  been made, sometimes things change there too. Great. So important to think about the research  components of this, of course. I know we're coming to the end of our time and I know that there's  still some questions, so if anybody wants in, the audience wants to send your questions  directly into CURE Epilepsy, feel free to do so at research@cureepilepsy.org. I want to thank Katie  for a great presentation. Thank you so much for breaking it all down for us and provid

ing answers  to the questions. I also want to always thank our amazing audience for all the great questions  you offer and get us thinking about what needs to happen next. Again, if you want to learn more  about CURE Epilepsy, our research programs or our webinars, please do visit our website. And again,  you can email us at researchatcureepilepsy.org. This is actually, again, as I said, the first  of two epilepsy genetic webinars this month and the registration has already begun for  our second

webinar, which is focused on genetic testing for adults and specifically  how testing can help adults with epilepsy and their diagnostic odyssey and in some cases  identify new treatment plans for their epilepsy. That webinar is going to be hosted on March  22nd and will feature doctors gemma Carville and Elizabeth Gerard, who lead the Adult  Epilepsy Genetics Clinic at Northwestern Medicine in Chicago, Illinois. You can scan the  QR code right on your screen and it will take you right to the w

ebinar registration page.  I encourage you to do that. And each of you who are on the webinar today will receive a  follow-up email with a link to register for the webinar if that's more convenient for you. So thank you all again for your participation and especially Katie for all your information  and we hope you have a great day. Thank you.