Our SWAN/RGI Transcript is finally ready (see below)! As mentioned before, the unanswered questions will still be answered- they are in the works!
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AMY : Welcome, everyone. I’m Amy Clugston from Syndromes Without A Name USA, or SWAN USA for short. Thank you for joining us on our first conference call of “Ask The Expert.” Thanks to the Rare Genomics Institute team for their work on bringing this opportunity to our community. A quick disclaimer for you all today on this conference call: we will be sharing a lot of information — this information should be used for educational purposes and should not be considered a replacement for consultation with a healthcare provider. So contact your healthcare provider if you have questions about your health. Let’s welcome our panelists.
Jimmy Lin. He is the president of RGI and he founded the Rare Genomics Institute. He received his MD and PhD from John Hopkins School of Medicine and is an expert in next-generation sequencing and cancer genomics. He is a 2012 TED fellow.
Marisa Dolled-Filhart. She is Vice President of Strategic Alliance and Partnership for RGI. She received her PhD from Yale University in Genetics. She has several years of operational and strategy experience from scientific and business development positions at HistoRx and Quintiles, focused on personalized medicine.
Naira Rezende is the Vice President of Patient Advocacy and Polices for RGI. She is a PhD candidate in Molecular Biology at Cornell University. She has been a research fellow at many prestigious research institutions, such as Yale and MIT.
Would either of you like to share anything about yourself today?
JIMMY : No. Thanks for inviting us!
AMY : OK. So I’m going to start by asking pre-submitted questions that some of you might have shared with us previously to this conference call. That will be for the first 45 minutes. During that time, you’re welcome to post questions on RGI’s Facebook page at facebook.com/raregenomics. You can comment on the post that is currently being posted. And you could send a message if you would like it to feel a little more private. We will then spend 15 minutes answering those questions that were posted. If the questions are too specific, we will try to answer them in a general way. And RGI will answer them individually as well. All questions that haven’t been answered on the call today will be answered and posted on RGI’s website. So let’s get started with those questions. We will start with, “How many people in the world have rare diseases currently diagnosed?” Jimmy, would you like to take that one?
JIMMY : Yes. Thanks, Amy. Again, I just want to say thank you for inviting us — this opportunity to partner together and hopefully we’ll be able to answer some of the pressing questions that the patients have. So, yes… the first question… ”How many people in the world have rare diseases? Are rare diseases really rare?” And that’s a great question. Rare diseases are rare in themselves. There are over 7,000 rare diseases and in the U.S., it’s sort of a legal definition. If less than 200,000 people have it, then it’s considered a rare disease. And most specifically for them having special status when they’re developing drugs. However, the 7,000 diseases when added up together affect tens of millions. In fact, it’s almost — in the U.S: 1 in 10 people have rare diseases. So in the world, the global number is about 350 million people with rare diseases. So although individually rare, rare diseases together are actually very common.
AMY : OK. Thank you, Jimmy. ”What kind of current medical technology is the most useful for rare genetic disease research?”
MARISA : There are a variety of methods that can be used for rare disease genetic research and in particular for diagnosing rare diseases. One of the most common method traditionally used is the family pedigree. So tracking the different relatives within a family, understanding who is affected by a disease and who is not- tracking of symptoms. Those are some of the basic components of rare disease diagnosis. However, there are a variety of medical technologies that can be used to help further study and identify and diagnose rare diseases. One of them is called karyotyping where the chromosomes of the person is looked at to see if there are any major chromosome changes or rearrangements that are different than what might be expected. And that is useful for identifying some large chromosome changes, but can miss some of the smaller changes. So there are some other methods that can be used as well which can give a bit higher-resolution look at chromosomes for rare diseases. And one of those is called Array-CGH, where CGH stands for comparative genomic hybridization. And that can look at chromosomes at a higher resolution, but not at the gene level. So some of what we’ll be focusing on discussing today are some of the latest advancements and technologies related to sequencing. We’re looking at the DNA at a base-pair, letter-by-letter method in order to look to see if there are any changes in the DNA or mutation that would be responsible for causing rare disease.
AMY : Thank you, Marisa. On to the next question, “Have there been any new advances in the past two years with the microarray testing?”
JIMMY : Yes. It’s a good question. Another question too is, “What kind of advances in general have been in genetics these days?” Like Marisa mentioned, the family pedigree is going to be very, very important, and that hasn’t changed. So that is more predictive than anything else. To karyotype some things on the chromosome level, when it’s large, hasn’t — it’s a broader, larger look. The things that are of higher density is microarray. What microarray does — it looks often at specific locations. And they have these chips that look at positions in the genome. And what has advanced is that more and more number of positions are now examined. It started out within a hundred of thousands, then half a million, now people can do over a million. So it is now higher density and allows for a deeper look and ultimately, I think, eventually we’ll be able to look at every single base pair using whole genome sequencing.
AMY : OK. To add on to that, “What has been available now that wasn’t in 1989? So what is the future progression for looking at signs and symptoms between what some other family members might be passing on?”
JIMMY : Yes. So there was specific that year of 1989 that the person who submitted the question asked for. And it’s interesting because it is humongous how much has happened since the year 2000, so 1989 is a while back. The human genome was sequenced about 10 years ago, around 2001. And since then, there has been a dramatic increase in the ability to sequence. Ten years ago, we sequenced the first human for $3 billion and now we can sequence for about $3,000. So sequencing is actually now a possibility for patients and there have been many, many advances since 1989, of which sequencing is one of them. I don’t think there was even microarray. Yes, there was no microarray in 1989. There was some simpler sort of chromosomal studies and karyotyping, but most of these technologies we are mentioning did not exist in 1989.
AMY : OK. Thank you, Jimmy. ”What are families to do after ruling out several syndromes and with two negative microarrays? Is it worth it for families to pursue continued genetic testing? Or have possibilities been exhausted at that point?”
NAIRA : Not yet. It is important for a family to continue pursuing this testing, and sequencing technologies are the way to identify a new patient-specific gene on a single base pair and to come up up as a diagnosis. One of the things that I want to explain on this answer is that microarrays and genome sequencing are fundamentally different. Both of them look at the genome and look at many, many genes at the same time. So both of them are more than just a single test looking at one mutation in one gene. But the way that they’re structured differs fundamentally. So in a microarray, you take a look at the genome and you hybridize it to a number of pre-established sequences. Even though it’s a global approach, there are a number of sequences that you are looking for, and you’re looking for a difference in expression between, let’s say, the mother’s genome and the child’s genome. What you get with sequencing technologies is that you get a specific base pair difference between the genome of the mother and the child. And that can give much more of an answer in diagnosis.
AMY : OK. To add on to that a bit, there are different devices for sequencing, and we’d like to know, “Which is better? What kind of sequencing methods are better and why? “
NAIRA : There are many different companies that make devices for sequencing. And most of the focus of sequencing right now really is in the analysis. When you’re doing the sequencing, what you’re going to get is the base pairs in their genomes, and what the scientists really are looking for are mutations when they compare the child’s genome with the genome of the parents, what really stands out are the differences. Illumina is one of the companies that makes such sequencing devices, Life Technologies is another. There is no definition right now in which one is better, and why each one is better. Sequencing is the most sophisticated approach that is out right now, and what you’re really focusing on now is the analysis of the data, which is one of the things that RGI has developed its scientific partnerships for. That way (with the scientific parnerships) the quality of the analysis of the data can be the highest possible, that means we can identify a mutation. The focus should not exactly be in which of the machines or the company that is used to be the sequencing.
AMY : OK. Thank you. So families — if they have already explored all these methods — what are their other options? They’ve seen many doctors, what else could they possibly do?
NAIRA : Genome sequencing right now has about a 30% success rate in identifying the causes of the disorder. This is actually higher than anything else that you can have with most of those undiagnosed diseases. That’s actually why — specifically why they should pursue genome sequencing because in many cases other methods have failed. I lead the advocacy team at RGI, and we speak to a lot of those families. It’s very common that a mother describes to me that they have been to five or six different clinical geneticists, have tried every single test they possibly can, and they still don’t have a diagnosis. They know that there’s a strong genetic component to it (the syndrome) because five or six clinical geneticists have evaluated (the child) and come to that conclusion, but they still don’t know what could be behind that. So that’s a perfect family that’s a perfect candidate for genome sequencing. And you do have now this 30% success rate in identifying the underlying causes of these disorders.
JIMMY : Yes. And then what’s amazing is that in the past, I think microarray and other methods are a great. Like karyotyping. I mean there’s things that they can find if there’s a larger change. Microarray can find large deletions, and what we’re specifically talking about are patients that have gone through traditional testing and have not found what has caused it. And that — of those, people have been able to use genome sequencing. And there’s some great programs that already do it. For example, the NIH has the UDP Program, which I believe — Amy, your family has been through — there’s also — University of Washington, there’s the Mendelian Centers, there are great places doing in it. And we at Rare Genomics are helping those who potentially are unable to connect to those places, or we provide some connections to those places. There are a lot of different possibilities, of which genome sequencing is one of the most powerful.
AMY : Thank you. OK. ”What is the difference between exome and whole genome sequencing?”
MARISA : That’s a great question, and I think a fairly common question. So the two main types of sequencing as you mentioned are exome and whole genome sequencing. What exome means is that there’s a portion of the genome that’s called the coding portion, that essentially scientists know is creating the genes that are used to create proteins, that are the functional aspects of our genome. And that represents about 1-2% of the genome. And historically, about 85% of diagnosed genetic diseases have involved mutations in this specific area called the coding area of the exome, within the genome. So essentially they’re short functional DNA sequences. And by focusing on just exomes and exome sequencing, it’s more efficient and more effective currently than whole genome sequencing, because you can imagine that with millions of base pairs of DNA, there’s a lot of information from a bioinformatic approach in order to identify the specific changes between parents and children that are occurring. They’re actually causing diseases compared to naturally-occurring variants in the DNA sequence. So one thing to know about exome sequencing, as I mentioned, it’s about 1-2% of the genome. There are some limitations to exome sequencing. So if for example there’s a disease that’s caused by changes in the structure or if there are mutations outside of the coding region, those are areas that wouldn’t be analyzed through exome sequencing. So that’s something to be aware of. However, the areas served outside of the exome, the function and the utility of those areas are not as well-known and we hope that there will be additional advances in our understanding of those areas through whole genome sequencing that can hopefully identify diseases that are not diagnosed through other traditional methods we’ve mentioned or through the use of whole exome sequencing. Whole genome sequencing, as I mentioned, looks at all those genes that we know have functions as well as less-studied portion. And hopefully in the future, the cost of whole genome sequencing will continue to go down and hopefully the informatics approaches that currently are more challenging with whole genome sequencing will be resolved so that that could be something that is used more routinely, the way that exome sequencing is starting to be used for diagnosing rare diseases.
JIMMY : So I think a good way to think about it, I just came off a plane. So I sort of have this image in my head of — I’m flying over the Midwest and most of it is prairie lands and there’s certainly a — I mean, once in a while, we’re flying over sort of cities. Interestingly, your genome is mostly stuff that we actually don’t know and they’re actually not expressed. These are sort of mostly space. And then the genes that we’re talking about — actually comprise of only a very small part and which Marisa has talked about sort of between 1-2%. And within the genes, there’s specific parts of the genes that are expressed called exons. And those are the parts that potentially are the things — the parts that we understand most. So what scientists are doing now is, first, focusing on those areas where we think there’s a high concentration of function and only a very small proportion of the genome. But those are the areas you understand most. And then later, as technologies get better, when we can look at the whole thing, so while sequencing is still not super cheap, we’ll emphasized on the most important part which is the exomes. And all the exons together is called the exome.
MARISA : One other thing to mention — I’m thinking about Jimmy’s analogy to looking at the U.S. from a plane — is that you can think about some of the different methods we’ve been talking about for genetic analysis and for use in diagnosing rare diseases in that same type of context. So if you’re flying in a plane and you’re looking down a city in the U.S., you can see that as — if you’re looking for a red car on the street — you’re using karyotyping. It will let you know if there’s a lot of red cars, or if there are blue cars instead of red cars, or see something sort of major — something that you can really view from high up above, and that is kind of what karyotyping does, is let you understand sort of some major changes or show if there’s a big large crowd of red cars, you would see it. At the next level of some of these microarray technologies, where it’s not so much about looking from the plane instead of just seeing sort of large expanse of country. You can kind of zoom in on a part of the city. So higher resolution. You might be able to see that there are sort of a lot of large buildings, or if you’re flying at night time, you see a huge cluster of lights but you may not be able to see things individually. And so then if you zoom in further, you can see sequencing as being able to see a single red car driving on the street. And that kind of gives you the different levels of resolution that are possible with genetic analysis. And so as technology has advanced, it allows us to zoom in closer and closer, where they may be some disorders in which a low-resolution, or just looking outside of the plane window is sufficient to identify a major change that’s causing disease. Or in some cases, for other rare diseases you really have to zoom in to that sort of individual car from a plane level in order to be able to identify a change that is causing a disease.
AMY : OK. Thank you very much. Great description. So, “How does this work? Why do we need to sequence parents?”
JIMMY : Yes. Often, when we do sequencing, we don’t just sequence the child, because on average, everybody’s genome has a lot of changes. And what is a a good way of sort of subtracting those changes is a child gets half of their genome from mom, half their genome from dad. And they can compare if that gene comes from mom or comes from dad, and mom and dad are OK, that sort of change probably — if it’s also a mom and dad is probably not what caused the disease, if it’s a very — what’s called the penetrative, if that’s the change has causes a big deal. If it causes a big deal but it’s also in mom and dad, and mom and dad are healthy, then that way they could subtract. So genome sequencing is very good because you can — there’s a lot of changes, right? If you imagine two maps, we’re talking about from the plane, there’s often a lot of changes in every person, so then important thing is from all those changes that exist, the whole genome holds tens of thousands, which of them actually are important and which of them cause disease. So what we do is we sequence mom and dad. Take a one out of mom and dad. Then we compare them with the general population, and see whether they exist in the general population, if they exist in high frequency, they’re probably not a disease. And then from the ones that are left we then look at, “You know what? Which ones are the ones that are broken? And do we know that the gene that’s broken does something specific that’s related to the disease?” And from that process, we can sort of then shorten the list to sort out top candidates that we think are potentially causative of a child’s disease.
MARISA : Jimmy makes a good point about some of the different changes that occur. Some of them maybe sort of more naturally occurring variants that may exist in the general population. But you also mentioned thinking about genes that are “broken.” So what that means is that sometimes when there’s a change in the DNA sequence, ultimately the DNA sequence is used to create proteins and so you can think about it in the sense that in some cases there may be a change that doesn’t ultimately have an effect. So can be almost sort of like an ineffective… or a change that doesn’t actually impact the resulting proteins. However, there are some changes that could then end up causing the proteins to be shorter than it should usually be, or have a different amino acid that would somehow change the structure or the formation of the protein. And so by not only filtering the sequence comparison between the parents and the child against the general population that is unaffected by this disease. You can also look for the types of changes, whether there would be deleterious or not or sort of causing problems or not. And that can help, as Jimmy mentioned, narrow down the list of what maybe a disease-causing mutation or what may not be a disease-causing mutation based on how strong the impact is of that change to the end results of that sequence.
JIMMY : Yes. So the same change in different parts of the genome can cause sometimes big effect and sometimes no effect. When it’s causing no effects sometime it’s called silent. Maybe we can use analogy of a car; in St. Louis we had a hailstorm and that caused a lot of damage to cars. If the cars are hit a little bit on the roof and it causes a small dent, I mean, you can still drive the car. It’s not a big deal. But for some unlucky people, for example, if they land on the glass, it will crack it. So that causes a problem. Then I had a very unlucky friend who had hail like right at the juncture where the trunk opens. So they have to change their entire trunk and that was a big deal. So when a change like that happens, like on a genome, when it’s on like the hinge of the trunk, it causes a big problem. So in the same way, in the genome, depending on where those changes are, sometimes it could… everybody has a lot of different changes on the genome. Some of them actually cause some effect. But then there’s a few of them that really sort of cause functional differences and often are ones that cause disease. And those are the ones that we’re looking for and potentially are the ones that may cause this disease in these kids are hoping to help.
MARISA : Another thing to mention is that for a lot of sort of traditional methods of looking at genome-wide for genes that are associated with disease, a lot of times it requires very large family pedigrees and large cohorts of patients in which there are high numbers of both affected and unaffected patients. The benefit of sequencing is that you don’t need as many family members or as many affected individuals in order to still potentially get useful information. So just by sequencing the parents and the child, it can potentially be enough information in order to try and identify a disease-causing change. And that’s one of the benefits compared to some of the traditional methods that require a large population and specifically for diseases that are rare, or where there aren’t other affected family members, where the disorder is unique to just a single member of the family. These types of advancement in technology can be very useful.
AMY : Thank you. ”And how long does this genetic testing take?”
NAIRA : For the analysis stage, it’s a very long time. And when you think of the analogy that Marisa and Jimmy were telling, it really depends on how obvious the difference is. If it’s very obvious, think of the cars in the hail. If it’s very obvious that you have a big damage to the crust, then it will be easy to find. If it’s not very obvious, you’re going to have to look a little longer. So it can take up to one year. And it really depends on how obvious the mutation is. Now, if you’re missing a very big chunk of your DNA, it might be easier for the scientist to find it. The way the process is structured, you schedule an appointment with a clinical geneticist and it usually takes about two to three to four months to get an appointment with a clinical geneticist. Sometimes, up to six months. And after this clinical geneticist determines you are a good patient for genome sequencing, and it’s likely that there’s a genetic component to what’s affecting your child, then it can take up to one year for the analysis to be performed. And keep in mind that this analogy: if the mutation is very obvious, think of these cars that were in this hail. If there’s a lot of damage to the roof of the car, it might be easy to see instead of a tiny little dent.
JIMMY : Yes. What’s interesting though is that actual testing can be fast. They’re predicting that by the end of this year, actually, to be able to sequence an entire genome for a $1000 in a day. So theoretically, we can get the sequence in a day. However, it takes a long time for you to see the doctor. Patients know sometimes it takes a long time to go and see a doctor. And then the doctor say yes and they will participate in the study, and then you wait for a space on the machine. Once you switch on the machine, it takes a day. But then, that’s only the letters. That’s only the codes. Then it takes time to decode that. And like Naira said, sometimes if it’s really obvious, we can decode it very quickly. Sometimes if it’s less obvious, it could take a long time. And so it’s really variable. And so the timeline we’re using over in Rare Genomics, we estimate on average, from patient contacting us, seeing a doctor for the first time, during the project, it could take up to a year and we’re trying to make it shorter when we can and shorter as possible. And hopefully we can shorten it. And that’s one of our things that we’re trying very, very hard to do. But a lot of advancement is going on.
NAIRA : One of the things to keep in mind is that the technology we’re developing to analyze the data is getting better, so the tendency for the data analysis portion of it is that the time can actually decrease with time. Right now it can take about a year to analyze the data. Maybe less, maybe more. But the tendency is for this time to decrease.
AMY : Thank you. We have another question, “If a family has an idea of what kind of gene is causing the problem, why do they recommend doing whole genome sequencing anyway, and what is the benefit of the sequencing?”
MARISA : So the benefit of sequencing in this case is actually to confirm that the gene that is suspected of being involved with this disease is actually the one that’s mutated or is causing the disorder. And so sequencing can be used to confirm this mutation, and that can be very helpful in confirming the diagnosis and confirming a specific gene that is involved. In some cases there can be a disorder where there are multiple genes in which a mutation, any one of those genes may cause particular disease and symptoms. In other cases it may be a mutation in just one gene that is really causing the disease, for another disorder. So one thing to be aware of is that as we’ve been mentioning, while the sequencing itself can be rapid, it’s the interpretation and the identification of what’s actually causing disease that can be challenging. In some cases, even with rare diseases, what can be helpful is if there have been previous patients that have had similar symptoms and medical issues that also have a mutation in that gene. That can help establish that particular gene as being causative of that disease. But in other cases, it may not necessarily be fully possible to definitively identify which gene may be causing the disorder and some other research or investigation may be needed to further characterize these genes and try to identify which genes may be causing these symptoms and the characteristics of the disorder that are being done. But what I would say is the main advantage to knowing what specific gene it is as compared to sort of a generalized idea of what kind of gene there’s a problem with is, if there is no treatment available or if there is treatment available, treatment available may be dependent on what the specific mutation is, or there may be some research options or treatment possibility options that would be very dependent on knowing specifically what gene is being impacted. So we feel that it is as important as possible to try and identify this specific gene even if the current state of research doesn’t represent options for treatment. Just knowing that information could be helpful in further advancing research as well as the advancement of further treatment options.
JIMMY : So for this patient or family who’s asking this question, maybe they think that they already know what the gene is. I think the recommendation of — again, the disclaimer that we’re not offering medical advice, but for our patient, I think a doctor would often — so this is not advice — a doctor would often as he tries to sequence that gene particularly first, to see whether that’s the gene that caused the disease. And very famous example, hemophilia. There’s a specific gene. Or sickle cell, or cystic fibrosis. He would start off by testing that gene. And that’s often for a lot of these diseases that that gene is what’s wrong. But for a lot of — even for these diseases with a known gene, often, people would turn out negative for that. And then you would have to sort of figure out what other genes are potentially causative. For example, Rett syndrome, it has whole bunch of possible genes that potentially could be causing it. Right now I think about two or three potentially — but then still a large population is negative for those genes. So in those instances where we really haven’t sort of found what gene that’s broken, a wider sequencing effort is often helpful and what is traditionally done is they do a gene panel. So a group of maybe 10, 20, sometimes maybe 30 genes that are also sequenced, either in serial or in parallel. But now it’s almost more cost-effective to sequence the whole exome, or tens of thousands of genes at the same time. So that’s definitely a decision to be made by a doctor, but single genes — if they think it is a single gene potentially, a doctor could just test that one first. And if that’s a negative, to have sort of larger and larger sets.
AMY : Great. ”Where can grant money be found for research, and how can people connect with researchers?”
NAIRA : Now that’s a great question and that’s what RGI does. That’s why we founded Rare Genomics Institute. We want to connect families with scientists and clinical geneticists who have the ability to offer genome sequencing, exome sequencing, for families who can use it for diagnostic purposes. There are many different ways that you can pay for the project, and depending on the site, it might be eligible for grant money. Grants are written in very specific ways, and sometimes they may cover of a particular type of disease. Let’s say, a grant may cover a blood-related disorder, and it may cover a more specific disorder. But not every grant will cover every case. There are many other ways of paying for it. Some commercial insurance companies have been reimbursing families for sequencing. This is very new and we’re always very afraid of promising a family that they can get reimbursement from commercial insurance because this is just happening right now. One of the things we have done as a non-profit organization is set up a crowdfunding page on our website. And if you don’t know what crowdfunding is, go to Rare Genomics page on the Internet, and it’s raregenomics.org, and then you click the link that says “Our Patients.” By clicking on that link, you can see some of the families that we have been able to help by crowd funding resources to pay for the genome sequencing projects. Some families have approached us and they have said, “You know, I can pay for it myself. I just really need your help finding the scientist and finding the clinical geneticist that can give me access to this technology.” So that’s one of the things we do and that’s one of the things we’re good at — connecting families with the people who have the ability to do this for them and who are like, ahead of the technology.
JIMMY : I think what we hoped, really, is either this kind of service can be covered by insurance or there are existing grants for that. But the reality is a lot of people aren’t eligible, but they still want to get this done. And some people are able to pay but I think that’s sort of a smaller minority and we don’t want people to mortgage houses and sell cars, and that’s why we thought of this idea of crowdfunding as something very exciting where we can set up a page for a patient, and then you can tell your friends through social media, through different things, and everybody gives a little. And together, right, it’s cheesy, it takes a village to raise a child, the cheesy sort thing that we say. It takes an entire community to do research for a child as well. So if everybody gives a little, then the entire community feels like they want pitch in a little bit, and then we can sort of fund research in that way. So crowdfunding is a method for if other methods don’t work and people really want to do this for their kids, and that’s the method that we are facilitating for that to happen.
AMY : Great. And we thank you for that. ”So what happens if something is found and no one has ever seen that disease before?”
NAIRA : I think that one of the exciting things about Rare Genomic is that we have this extensive network between scientists and clinical geneticists. And one of the things that get the scientific community very excited is when they feel that they can help someone. Like, scientists want to work on problems that are meaningful. They want to be able to answer questions that will help you, that will help the family. So if you identify something on the genome that’s the cause of the disease and no one has ever had it before, then RGI can help you get connected to scientists and physicians who may be able to help you.
AMY : OK. ”How many patients get a diagnosis from sequencing?”
JIMMY : Yes. I mean, that’s a hard thing to say in terms of actual numbers. But right now, within the scientific community, between 25 and 33%. We usually estimate within a quarter to a third of people can get some sort of diagnosis. And of those, actually, only a small minority of them actually gets some sort of treatment right away. So we don’t want to over-promise people that this is going to be sort of the silver bullet and their child is going to get well right away, but it does provide some sort of a hope in advancement where other methods have failed.
AMY : OK. So how about we look on our Facebook page and see if there’s any questions on there. Jimmy, can you take a look and see what that question is?
JIMMY : So people who have questions, again, go to our Facebook page, to just remind people that that’s www.facebook.com/raregenomics. Rare Genomics is spelled r-a-r-e-g-e-n-o-m-i-c-s. Raregenomics. And then you can post the question there. And then hopefully we’ll — if it’s sort of a general question, we’ll be able to answer it. So let’s take a look. There’s one question specifically about LEOPARD syndrome. Maybe we’ll get back to that. The question here is, “What is the difference between exome sequencing and mitoexome?” Hmmm…
MARISA : So I assume that mitoexome refers to mitochondrial DNA sequencing. I believe there’s a recent publication about this at the beginning of the year about the potential use as well as possible challenges of sequencing mitochondrial DNA. So there — I want to go and take a look — there’s a difference between exome and mitoexome. I’m not familiar with all the details of mitoexome sequencing but what I can share in general as far as mitochondrial DNA is that that’s something — so there’s DNA in the nuclei of ourselves. There’s also mitochondrial DNA which is typically inherited from the mother. And that is something where there has been a small number of diseases that have been identified based on mutations in mitochondrial DNA. I would say that is as far as my knowledge, I believe that exome and whole genome sequencing is something that has been gaining speed and is being used more than mitochondrial sequencing. But perhaps I can let Naira and Jimmy, some of the other experts on the panel, comment a little bit more about this.
JIMMY : Yes. So the mitochondria is a small organ within a cell. They thought maybe they used to be another sort of tiny cell, but they actually reproduce themselves and they help produce energy in the cell, and they have their own DNA. And for some diseases actually, it’s caused by problems in the mitochondria so then mitoexome sequencing is sequencing the exome (correction: AND) the mitochondria. The mitochondrial DNA is much smaller so actually for some diseases, they sequence the mitochondria pretty regularly. So sequencing the mitoexome, specifically at looking at diseases that potentially are in the mitochondria (CORRECTION: and) the exome versus generic exome sequencing which is the — sort of the exome of the human part of it. So that’s what the difference is. And mitochondrial sequencing, because it’s much smaller, it’s actually much easier and has been done in a clinical context much more pervasively than whole exome sequencing.
AMY : Jimmy, this is Amy. I’d like to jump in and ask a quick question on that. As you said, is there any potential in those two testing being available in one test, versus doing it separately?
JIMMY : Yes. I mean, that’s a good question. It depends on the design. What scientists are doing these days — exome sequencing is, they design little beads and this thing with little beads have like special velcro on them. This velcro is able to sort of stick to the part of the genome that is exome. So what you need to do is when you design these little beads with velcros is also capture the mitochondria exomes. It’s very feasible and it has been designed that way. Just currently it is not being designed that way, but you know, there’s no reason why not the future, people can do that. Right now, most of this is done as sort of two separate tests, the mitochondrial sequencing and then separately the exome genome sequencing or whole genome sequencing. Another thing, too, is actually you have a lot more mitochondria in your body. Every cell has a lot of mitochondria. There’s actually a variety of population. So there are different techniques actually. Sequencing the mitochondria versus a nuclear genome. So there’s a little bit of difference there, too, and potentially that’s why it’s split up into two separate tests.
AMY : OK. Thank you. So I don’t see any other questions posted on the Facebook page.
JIMMY : Maybe we can go to the other questions that we haven’t got to, that people submitted beforehand.
AMY : OK. Let’s see if we can go to those. So one question is, “How do we set up a medical record for an undiagnosed patient when their health is ever-changing?”
JIMMY : Yes. I mean, the medical record is going to be very, very important. And I think Naira has talked to a lot of patients about this. I think the doctor only knows as good as — they only get one snapshot, seeing the patient. And they rely very, very much on the medical record. So one of the first things that we tell patients when they do come to us and they’re trying to do something very extensive, is to organize their medical records. And actually, Amy, you could jump in here. You’ve organized medical records like a pro, right? What have you done for medical records?
AMY : Yes. There’s a few things out there that can be used. There’s some binders that families are using to help with just having the basic information to carry on to each doctor’s appointment. And then families choose different methods of keeping the records of all past appointments, but I do advise that families ask for their copy of the reports as they go to the doctors because sometimes we might catch something that we didn’t catch at the doctor’s appointment. So it’s good practice to get all those medical records that you can of families’ undiagnosed individual. And then some families like to collect them by date and others like to collect them by service provider. So it’s a matter of getting the records as the first priority and then how you organize them can be up to their personal decision.
NAIRA : Getting the medical records organized can help your clinical geneticist so much. And the more you help your clinical geneticist, the more you help yourself. Every time I help a family get an appointment, the doctors review those records very, very closely. And they want to know about you. They want to know about your child. They want to know about the history of how the symptoms of the syndrome have manifested and they look in that information for clues. What I was talking about earlier, the data analysis, is when the scientists are going through the data say, “If they have some clues on what to look for, the whole process is faster.” He could potentially — you could potentially find the answers sooner. So one of the first things that I tell families immediately after I connect them with a clinical geneticist is to get the medical records together and get as much information as they possibly can, bring them to your clinical geneticist, and have a discussion, have a frank discussion with them and that data could be used to help you and your family find an answer.
AMY : Thank you. That was a great answer. Just another question, “What resources are available to help people with rare and undiagnosed diseases find opportunities to participate in research?”
JIMMY : Yes. I mean, that’s a good question. And the difficulty is that there are so many different diseases that are out there and finding a specific research study for that is hard. Actually, recently, last year, an organization contacted us. Research Match, for example, is able to be a sort of clearing house to match different people. The NIH, I would think, the Office of Rare Diseases, and there’s a specific research network that you can then look whether your particular disease is one that’s being researched. And take a look there. And then Office of Rare Diseases also has a database called GARD, G-A-R-D that sometimes has a link to that. And then lastly, the European Registry actually has some good resources there. European Registry’s organization is called Eurodis. E-u-r-o-d-i-s. And then their database that a lot of people use called the Orphanet. It’s O-r-p-h-a-n-e-t. Orphanet. And sometimes Orphanet will have links for the specific diseases and then you might be able to find research opportunities there as well. And actually, Amy, you actually know about the resources since you do a lot of research for this.
AMY : There’s not a whole lot of resources out there actually. Some of the old ones that I used to use aren’t available anymore. So I think you pointed out some of the biggest resources there. And this information resources are constantly changing with just the different options out there for families like the UDP that’s come out and that’s a great resource. Just for having opportunities for families. So there’s really not a lot of resources. I’m hoping that there will be some more added, and RGI is an added resource and of course SWAN USA is a good resource for families who are trying to find information —
JIMMY : Yes. I forgot to mention two very important organizations myself. Of course, NORD, a national organization of rare diseases, and Genetic Alliance. Genetic Alliance is great for groups wanting to set up new groups for that. And NORD also has been great in terms of pushing for advocacy. And then one more — we have — there was one question that we haven’t gone to, I just sort of skipped to, about a database for gene tests. So, yes, there’s NIH site called Gene Tests, and you can just Google that. And you can look at the different tests that potentially could relate to your disease. And mostly, it’s actually used by doctors, but if you’re interested in that.
AMY : Great.
JIMMY : Let’s do one more question. How’s that?
AMY : OK.
JIMMY : Before we end.
AMY : OK. One more question. Do you want to pick one more question or do you —
JIMMY : No. You can pick.
AMY : OK.
JIMMY : Let’s get to the other ones. Just for people who are on — who have submitted questions that we don’t answer, we’ll eventually answer them.
AMY : OK. Do you think anyone can answer this one — “When and how is a rare disease or rare genetic disorder named?”
JIMMY : Yes. I mean, multiple people have asked us this. And it really depends on a lot of things. So some diseases for example, are named by the process that caused it. For example — let’s talk about PKU for example. Phenylketonuria. In the urine, there’s phenylketones, that’s the name, sort of the descriptive name — but interestingly, if you’re overseas or are actually in Europe, it’s actually named after the discoverer, in terms of that disease. So even from sort of between country and country, the name could be different. Sometimes, it’s named after a patient. Sometimes it’s named after the doctor who’s found it. Sometimes it’s named after the region that the disease is discovered in as well. So there’s no sort of — I think it’s as personal as parents naming their kids. Sometimes researchers just name the disease as they find it. So I think hopefully that — those are some of the reasons — no, ways that people are able to name diseases.
AMY : Thank you. I think a lot of families often feel like their child’s condition, could be named after their child because they’re the one and only one with their kind of specific signs and symptoms. So we often use in our community that our child has “their-name” Syndrome, after their name. We often do that in our community.
JIMMY : Well, in the future, I mean, ultimately, everybody’s sickness is going to be very, very individualized and different, and really, all medicines should be individualized and personalized. So maybe that is the way to think about it. It’s a group of diseases but then really, it’s just like in cancer, for example. I mean, they’re personalizing cancer. So it’s not just breast cancer, it will say it’s Mary’s Breast Cancer. Or it’s Sarah’s Breast Cancer. So maybe you can think about rare diseases in that context.
AMY : Great. OK. Well, I thank everyone for joining us. It’s been a great call today. And we will be looking into seeing how this went and seeing as we might provide more conference call in the future. So thank you for calling in. Have a good evening.
JIMMY : Thank you.
AMY : Ba-bye.
NAIRA : Thank you.
MARISA : Thank you.
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