[00:00:03] Speaker A: Hello and welcome to this edition of Cook Children's Dog Talk. Today we're talking about diagnostic mysteries, the secrets in our DNA and optical genome mapping with doctor Diana Carrasco and Doctor Nikhil Sahajpal. Doctor Diana Carrasco is a pediatric clinical geneticist here at Cook Children's. She completed her residency at Baylor College of Medicine in Houston as the clinical genetics lead for Cook Children's precision medicine program. Doctor Carrasco is powered about improving the diagnostic rate and time to diagnoses for genetics patients. In this role, she hopes to bridge the gap between clinical care and research so that patients can benefit from cutting edge technology.
Doctor Nikhil Sahaspal is a laboratory genetics and genomics fellow at the Greenwood Genetics center in South Carolina and is a recipient of the ACMGLG Next Generation Fellowship Award by the American College of Medical Genetics Foundation. Doctor Sahaj Pal has a keen interest in rare disorders and birth defects, with a focus to understand the genetic basis of these conditions. Welcome.
[00:01:12] Speaker B: Thank you so much for having us.
[00:01:14] Speaker C: Thank you for having us.
[00:01:15] Speaker A: So let's start with what attracted each of you to the field of clinical genetics and a little bit about your collaboration.
[00:01:22] Speaker B: So when I was in medical school, my histology professor introduced my class to one of my favorite poems by Alfred Tennyson. And it's called flower in the crannied wall. And I bring it up because it reminds me of why I love genetics. It reads, flower in the crannied wall. I pluck you out of the crannies. I hold you here, root and all in my hand, little flower. But if I could understand what you are, root and all and all and all, I should know what God and man is. And for me, our DNA is the flower in the crannied wall that allows us to best understand our patients. As geneticists, we see children with developmental conditions, neurologic diseases, birth defects, and medical concerns that seemingly have no explanation. Our job is to look deeply into their DNA to see if we can find a genetic cause for their concerns. So in this way, a geneticist is like a detective whose job it is to solve diagnostic mysteries. The detective work is a part I enjoy the most about what I do.
[00:02:24] Speaker C: I think for me, it was also my mentors that attracted me to this field. I think I was fascinated by the fact that there is something that we hold that is a blueprint to who we are. That realization itself led me to pursue this field as my career or a life choice, per se.
[00:02:41] Speaker A: And sue, how did you guys get together and form your collaboration?
[00:02:46] Speaker B: I had heard about optical genome mapping as an emerging technology in our field and its great potential to potentially detect variants that other testing technology cannot detect. And then I saw a virtual conference that Doctor Sahas pal presented in, and I found his email and reached out to him about possibly establishing a collaboration between Cook and the Greenwood Genetics center where we might be able to offer this technology to some of our undiagnosed patients.
[00:03:22] Speaker C: Yeah, I think like minded people come together. Every geneticist is having a quest to find answers and every opportunity that there might be to increase the ability to find answers or to increase the diagnostic yield in the patient population that we serve. And that's the basis of how we came together, is to advance the genetic testing that we offer to our patients and have a higher diagnostic yield.
[00:03:50] Speaker A: This is such a fascinating topic. So to orient our listeners, can you give us a back to basics introduction to genetics?
[00:03:58] Speaker B: Yes, and I'm going to go way back to basics, and this might be too basic for some of our listeners, but I always find that before we get into the nitty gritty of things, it can be helpful to do that. Our hereditary material is called DNA, and we all inherit our DNA from our biological parents. We get 23 chromosomes from our mother and 23 chromosomes from our father. And our DNA is like a recipe book. It has instructions for how our body works. But instead of being written with the 20 letters of the Alphabet, it's written with four letters or nucleotides, which are adenine, guanine, cytosine, and thymine. And whenever there's a change in our DNA, we call that a variant, we can compare a change in our DNA to a typo. Some variants can be compared to whole deletion or duplication of paragraphs in a book. There's many, many different types of variants. Variants are classified according to whether they cause disease or not. So a pathogenic variant is a variant that can lead to medical disease. A likely pathogenic variant is a variant that, with more than 90% likelihood can lead to a disease. A benign variant is a variant that does not lead to disease. And those are the variants that make each of us different. And then likely benign means more than 90% likelihood of being benign. There's also a category called variance of uncertain significance, and that means that testing has detected a variant that we just don't know enough about to be able to conclusively say whether it's pathogenic or benign. And those classifications are based on the American College of Medical Genetics and Genomics and the association for Molecular Pathology guidelines that were published in 2015. And they were published by a group of experts in the field. And we hope that new, updated guidelines will be coming soon. And so when we see patients in the genetics clinic, our job is to order the genetic test that is most likely to detect the type of variant that might be causing their disease. And there's many different types of genetic tests to choose from. No one test is able to detect all variants. And then aside from variants, there are other changes in our DNA that can cause disease, like methylation abnormalities.
[00:06:19] Speaker A: Doctor Sajpahal, can you tell us more about the types of changes in DNA that can lead to medical conditions?
[00:06:25] Speaker C: Yes. So how? Doctor Koresco was saying there are several types of changes that can lead to a medical condition. We can start with the largest changes, which we refer to as chromosomal changes, or aneuploidies, which is a missing or an additional chromosome. For example, there can be a loss of chromosomes, such as loss of chromosome x, that results in a condition called Turner syndrome. And then there can be a gain of a chromosome, an additional copy of chromosome 21, which we refer to as down syndrome. Then there are copy number variations or copy number changes, which is missing, or additional pieces of DNA. An example of this would be Dejor syndrome, which is caused by deletion of a portion of DNA on a specific chromosome, chromosome 22, and we refer to that region as q 11.2. Then instead of the whole region, there can be just a missing gene or an additional piece of a gene. These are referred to as single gene deletion or duplications. An example of that would be duplication of the gene PMP 22, which results in char Kumari tooth. Then instead of a single copy duplication or deletion of a gene, there can be spelling errors in a gene. We refer to these as single nucleotide variants. And to give an example of this, the most historic example is the variant called f 508 del, which is the lesion in the gene CFTR and single amino acid deletion position 508, which results in a phenotype or a presentation of cystic fibrosis. Then apart from these, there are repeat expansion and repeat contraction disorders. An example of this would be fragile x disorder, which is one of the most common reason or cause for intellectual disability. Then there's repeat contraction, which would be d four, z four repeat contractions in the gene duct spore that results in the condition called FshDev. Then what doctor Koresco was referring to, that there can be changes which are not in the content of the genomic DNA but is how the DNA is packaged, which we refer to as the epigenome. So there can be changes in the epigenome, and we refer to these as imprinting disorders. An example of this would be Beckwith Weatherman syndrome, Russell Silver syndrome, and so on. Then since we are talking more about rare disorders, these genetic changes are germline changes. They most often occur in the germline, but they can also occur in somatic cells or during post fertilization periods. We refer to these as mosaic variants. The most common example of these are changes in the gene Pik three ca, which would result in PIK three ca gene related disorders. And then there can be changes in the genetic composition or the gene body, the genomic content, which is not in the nucleus, which is actually in a different cell, organelles referred to as mitochondria, and the changes in the mitochondrial DNA will result in a specific set of disorders. An example is Ali syndrome. So there's several different types of variations for which different tests might be ordered.
[00:09:42] Speaker A: So what are some of the most common genetic tests used in the genetics clinic?
[00:09:47] Speaker C: The most common tests that are seen in a lab varies with respect to which part or which region of the world the lab is in. But I would say the most common genetic tests are routinely seen in a laboratory are chromosomal microarrays. Then there would be specific gene panels or exome sequencing. And more recently, we have been seeing an influx or a higher order of genome sequencing orders. Then, based on the presentation of the patient, their clinical signs and symptoms, more specific tests might be ordered, which we just discussed, such as epigenetic modifications for those sort of changes. And the conditions that result from those changes would be imprinting disorders such as Beckwith Widowman syndrome, Brussels Silver syndrome, or playwright syndrome. Then for specific repeat contraction expansion disorders, there might be specific tests which are ordered to per se identify those specific changes. But I would say the most common tests that we see are chromosomal microarrays and some form of next generation sequencing. Be it from panels going up to.
[00:10:52] Speaker A: Genomes, what kind of genetic changes can each of those tests detect?
[00:10:58] Speaker C: So if we start with chromosomal microarray, these tests look at what we call as chromosomal changes. These would be aneucloides, a loss of a chromosome or a gain of an additional copy of a chromosome. And then these are more specific for copy number variations where we see a gain of a certain region of a chromosome or loss of a certain region of chromosome, and they have a higher resolution than some of the historic cytogenetic tests, such as stereotyping in fish, and they can look at smaller regions of the chromosome, such as single gene deletion or single gene duplications. Then if you look at exome sequencing. So just to refer back to that example of a book, if we consider we have 46 chapters, how many of those chapters actually code? Or there's a summary of that book. So what we believe is that the summary is actually the coding sequence within that book, if we can refer to that analogy. So the coding sequence is only one to 2% of the entire book, of the entire genome. So exome sequencing is like just looking at that coding sequence or the summary of the book, and we would sequence or look at just one to 2% of the entire genome. Then, as we go to a broader test, such as genome sequencing, this would look at almost the entire genome, and it has the ability to pick what chromosomal microarray picks, and it also has an ability to pick what exome sequencing identifies. But in addition to that, it can look at what exome sequencing does not look at, which is some of the in between lines within that summary. So it can look at changes which are in the introns, not in the coding sequence, but which might cause a change in the coding sequence. So these are the main tests. But I would like to point here, since in the introduction we did mention the technology optical genome mapping. What these tests do not identify is something referred to as balanced chromosomal rearrangements. So these are changes which does not cause any copy number changes. They are balanced within the genome. And the type of structural variations that would come in this category would be translocations, inversions, insertions and inverted duplications. Knowing how the orientation of the duplicated material is important to identifying these balanced events. These are the varying classes which are beyond these technologies that are used regularly in the clinic. There's one technology that the most historic technology referred to as scary typing, which is still used to pick these changes. But the resolution of that technology is five megabases and beyond, which is to say that it can look at very large balance rearrangements, but cannot look at small balance rearrangements. So we have been missing these smaller balance rearrangements for a long time, and we think that there are answers that we would reach when we start looking at these smaller balance rearrangements. And that's how optical genome mapping fits into this clinical workup and in our discussion.
[00:14:03] Speaker A: So we really do come with an owner's guide or owner's manual. We just don't know how to read it all yet. Right.
So, Doctor Crosco, as a geneticist in clinic, how do you know which test to order for each patient?
[00:14:16] Speaker B: This is a really important topic, because sometimes the way I make a decision might be by reaching out to a laboratory geneticist. And that's where the relationship between the clinic and the lab is very important, though there are guidelines. So the American College of Medical Genetics and Genomics recommends exome, or genome, as a first tier test in cases of developmental delay, intellectual disability, and congenital anomalies. And I would say to our providers listening, if you have a patient with some of those concerns, and I would include neurologic disease, and that refer to genetics, and the earlier you refer, the better, because we want to try to find a diagnosis as quickly as possible for that patient. So exome and genome sequencing are pretty comprehensive tests. There are times when we would order a narrower or more targeted test, and we do that when we see a patient that has a readily recognizable condition. The easiest example that I can bring up is something like down syndrome. And so down syndrome is caused by extra material of chromosome 21, and chromosome analysis would be the best test in that situation. Other disorders that are easy to recognize are things like Cornelia Delang, which includes terminal limb defects, or rosopathies, like Noonan syndrome, where children have short stature, pulmonary valve stenosis, and a broad webbed neck, and other features. So in those cases, I might order a panel that only includes the genes that are most likely to be involved. Doctor Sahaj Pal had talked about methylation disorders like Beckwith Weidamin. Others are Prader Willey Angelman syndrome. And so when we think we have a patient with that condition, we have to order that specific test to detect it. It requires having a higher clinical acumen. And then when we talk about mitochondrial conditions, whole genome sequencing, of course, includes mitochondrial DNA. But some signs of a mitochondrial condition are things like ptosis, external ophthalmoplegia, myopathies, deafness, exercise intolerance, cardiomyopathy, optic atrophy, pigmentary retinopathy, encephalopathy, seizures, stroke like episodes, ataxia, spasticity and chorea. And if we see that, maybe in combination with elevated lactic acid levels, elevated CK levels, then we would be suspicious of a mitochondrial condition. So, in summary, the type of medical concerns that my patient has tells me what kind of genetic alteration might be present in that patient. And that, in turn, helps me choose the test for that patient. There is publicly available genetic testing, stewardship, pathway on the Cook Children's website. If you just Google Cook children's clinical pathways, you'll be able to see a lot of pathways, including one titled genetic testing stewardship, which might be helpful for providers.
[00:17:20] Speaker A: That's fantastic. Thank you. So, Doctor Sajpahal, what are the most important things you need to know about a patient in order to have the best chance at finding a diagnosis? As a laboratory geneticist, I think I'll.
[00:17:32] Speaker C: Start with a quote that comes from a book that we refer to as our Bible. The book is genetics in medicine. And I apologize that I don't remember the author of the quote, but the quote goes by taking incomplete patient or family history is bad medicine. So you have to remember that a lab geneticist does not see the patient, but is the person who looks at the patient's genetic data. So what we rely upon is clinicians notes, the terms that they submit, that this patient has these clinical features. So we look at the genetic information and we match that genetic information to the clinical features that are listed by the clinician. So that's the key thing that we need or what we rely upon to reach a diagnosis. In many instances or circumstances, what we would do is instead of just running the patient genomic analysis, we run a do analysis or trio analysis, which is to say that we also run the parents. And what we look for is, if the parents are unaffected, do we see a change in the patient, which is a new change, which was not in the parents? So this is very important, having the right samples, having the right family members for doing the genetic testing. And to go back to my point of having the right history, what we would note in certain circumstances is that a change was inherited, which was listed as that the parent was unaffected. But when we go back and do a thorough clinical workup, we will find that one of the parents from which the change is coming is actually mildly affected. So that's a causal change. So having a right history, right patient samples, and the correct family members for doing the genetic testing is very important.
[00:19:22] Speaker B: I want to talk a little bit about that, because what Doctor Saheshval is pointing out is very important. As you can see, there are many factors that can impact the diagnostic yield of a test that happen or are provided to laboratory geneticists before any testing is done. And talking about the variant classification guidelines that a laboratory geneticist relies on to be able to tell us whether a patient's genetic variant is responsible for causing that patient's disease or not, some of the most important elements of those guidelines have to do with having very accurate patient phenotyping and relevant medical history. Relevant family history and geneticists work with genetic counselors. Together, we obtain the three generation pedigree for our patients and including relevant family members. So oftentimes when biological parents are available, it's very important to include their samples. Sometimes it might be relevant to include a patient's sibling or a more remote family member who has similar medical conditions concerns to our patient. All of that increases our chance at finding a diagnosis before any testing begins. Doctor Sajpal was also referring to the concept of phenotypic variability, where we might see a patient's parent who has maybe a very mild symptom that wouldn't raise flags for a geneticist. But when we consider it in the context of that child's medical concern concerns, then it could be suggestive of mendelian disorder that was passed on from parent to child. And in the parent, maybe that genetic condition expressed in a very mild way, but in the child, it expressed in a more severe way. And providing the lab with all of that information really helps them out. So that's why I would say it's also very important to involve the genetics team in decisions related to genetic testing. Genetic testing stewardship is a very important topic. It helps us utilize our resources in the most efficient way possible, and it helps improve patient outcomes.
[00:21:31] Speaker A: So it sounds like you have a wide variety of genetic tests available. Using this technology, I imagine you are able to find a diagnosis for a large majority of your patients. Is this true?
[00:21:42] Speaker B: Some studies have shown that, on average, pediatric patients and their families spend up to five years searching for a diagnosis, undergo five uninformative medical tests, and incur $10,000 or more in healthcare costs before reaching a diagnosis. Using our current knowledge and technology, we are able to find a diagnosis for about 40% of our patients. That means that we have not found an explanation for the medical concerns in as many as 60% of the children we see. And the reasons for that are varied. They include technological limitations of current tests. We also know that, on average, it might take up to 17 years to translate a novel research finding into routine clinical practice. And that's not just in genetics, but in medicine in general. And it takes that amount of time because new technologies need to be validated, professionals need to be educated on their use. And so all of that accounts for that time lag.
[00:22:45] Speaker A: So what is the importance of finding a diagnosis?
[00:22:50] Speaker B: Finding a diagnosis helps us understand why a child developed the medical condition they have. Why was a neonate born with a severe congenital heart defect? Why is a child experiencing debilitating immune dysregulation disorders? Or why do they have renal function issues? It's very important for families to find an explanation about that. It helps us have a better understanding as well of what a patient might expect in the future, because if we find a diagnosis, we do a comprehensive literature review about that genetic condition, and we see what kind of information has been published about patients with that condition and their age ranges. So that helps us give parents important information. There are also clinical care guidelines that might apply. So, for example, one of the multidisciplinary clinics that we have at Cook Children's is the 22 q one one two deletion clinic. And there are very updated guidelines about the specific type of medical care a child with that deletion needs throughout their lifetime. Of course, as a children's hospital, we rely on the pediatric guidelines, and there are also adult guidelines. It allows families to be connected to a community as well. Establish a relationship with other families who might have children with the same genetic condition. Reach out to specific foundations or societies that focus on their child's genetic condition. Parents can also have important information that helps them with family planning. They may be able to know how likely it is that if they have another child, that child will have the same genetic condition, and whether they might want to make use of seeing a fertility specialist or treatments like IVF. We learn more about rare diseases by diagnosing them. So, in aggregate, rare disease affects about 10% of the population in the United States. The more we're able to diagnose patients, the more we're able to contribute to the medical literature for those rare diseases and have a better understanding of how to manage those patients. And then, very importantly, finding a diagnosis is the first step in being able to find possibly a cure for that diagnosis.
[00:25:06] Speaker C: I would like to add something to what doctor Caresco just referred to. I think finding treatment is very important, and that's where the next frontier is. But something what doctor Caresco referred to in her answer to this question was guidelines on management. I think those are very important, and just to give some context to that. So there have been natural history studies done, which is when we identified patients with a specific syndrome or disorder, they were followed for several years as to see how they progress, which changes or which conditions, which abnormalities would happen at specific periods of time. So that now, when a new patient is identified with a specific syndrome or disorder, we would know that these are the conditions or changes that we need to monitor for. So we would know that at age three this individual might develop this particular clinical feature or phenotype. At age eight might develop this. So the families are prepared for what is to come. So I think that's very important. Even when for conditions where we do not have a treatment to having these management guidelines is very important for the patients and their families.
[00:26:21] Speaker A: Very similar to the Prader Willi Clinic that we have here at Cook Children's where the parents that are connected now because they can share that support and then they can also start to learn what to expect at each phase and it takes a little bit of pressure off. This is a lot of pressure on parents to have some of these conditions and on the families. So financially, emotionally. So, yeah, so this is fantastic. Thank you.
[00:26:43] Speaker C: This was a really good point because those support groups are very important and many a times we have these clinics, engineman syndrome and more common genetic disorders where there are patients in hundreds and the families can connect. But then there are such rare disorders that do not have a common clinical presentation. They are the same disorder because of the changes that have been found in the same gene. So it's genotype first approach that the disorder is characterized from what has been found in the genetic information rather than a common clinical presentation. And there might be just a handful, less than ten individuals around the world. So having a connection, knowing that there's someone else out there managing the same thing, it's very important for those families to be connected and go from there. So I think that's a very important point to be highlighted over there.
[00:27:34] Speaker A: So will the precision medicine program at Cook Children's help in this regard?
[00:27:38] Speaker B: Yes, I hope so. And I'm really excited about the precision medicine program at Cook Children's. It came about as an endowed chair that was awarded to Doctor Anish Raydhe and what Doctor Ray done is he's united the pharmacogenomics research, Clinical genetics and oncology departments with the common goal of providing our patients with individualized care in the clinical genetics department. We hope that we can increase our contributions to the medical literature through the Precision medicine program resources and build collaborations with various institutions that can allow our patients access to a wide array of testing options. Options. Our goal is to increase diagnostic rates, decrease time to diagnoses and connect patients with relevant clinical trials or research projects that target their genetic condition.
[00:28:27] Speaker A: What are some barriers you've encountered in reaching a diagnosis for your patients?
[00:28:32] Speaker B: One of the barriers might be limited access to care. If there are any students listening, please look into pursuing a career in medical genetics laboratory. Genetics genetic counseling is really a very fulfilling career, I can say. And it seems like over time, the genetics caseload, the number of patients who need to see a geneticist, is increasing. But the number of geneticists is not. Another important barrier is cost. Some of the out of pocket costs for these tests can be as much as 2500 or more. And some patients don't have access to insurance that can cover that. Sometimes insurance might take some time to extend coverage. So, for example, in 2010, a chromosomal microarray was recommended as first year testing in children with things like birth defects or developmental delay. But it wasn't until 2021 that a CMA was added to the Texas Medicaid schedule. And then by that time, the American College of Medical Genetics and Genomics was recommending exome and genome sequencing as first year testing for neurodevelopmental conditions and birth defects. So those time lags can present a lot of barriers in helping us help our patients. There's been increasing literature about the cost effectiveness of things like exome and genome sequencing. These are tests that are still not covered by many payers and many other tests that include things like genome wide methylation analysis. The Greenwood Genetics center has one called epic complete and other tests that maybe detect mosaic variants. Some of these tests are very difficult to get coverage for. And then other barriers are things related to racially and ethnically minoritized groups. So we know that these groups participate in research at much lower rates than majority populations, which means that we know less about their genetic material, less about what variants are important in causing disease in those groups, they make up a smaller fraction of cases in genomic databases. And genomic databases are some of the most important resources that clinical and laboratory geneticists rely on to decipher a patient's genetic information. For example, there was one pan assembly of the genome where 10% of african DNA sequences were missing from that reference genome. That's a very large amount, and that can lead to increased rates. Also a variance of uncertain significance, which means we found a variant in your DNA, but we just don't know enough about it to be able to tell you whether it does not cause disease or it does cause disease. So we really need to do more as a field to advance equitable care.
[00:31:23] Speaker A: So it seems like there's extra cost to not being able to diagnose something more thoroughly because there's constant attempts at trying to find out why your child is ill or why your child has these certain things. So you're paying all of this money and going to different doctors and different treatments and therapies without really ever resolving what's at the cause of it.
[00:31:44] Speaker B: Yes, that's exactly right. And there's many papers written on the cost effectiveness of both exome and genome sequencing and specific clinical situations for that reason.
[00:31:53] Speaker A: So, Doctor Sajpahal, talk a little bit about the reference genome. What is it?
[00:31:59] Speaker C: So, a reference genome is an accepted representation of the human genome sequence that is used by a geneticist as a standard for comparison of DNA sequence generated during testing. So you have to remember that when we are looking at a patient genomic information, we are trying to look for a change that causes a particular disorder or the syndrome that the patient presents with. Now, if we talk about general human variation, the earlier estimates were that 99.9% of the human DNA content is similar between two individuals. So to say that the difference between two individuals is just 0.1% of the genetic information or the genetic content, what we know now is that that's not true. We know that at least 2% variation is there between two individuals. So that's just a natural variation. That's what makes us unique. And when we are looking at clinical genetics, we are not looking for that natural variation. We are looking for that variation that causes a syndrome that is causal for the phenotype that the patient presents with. So for that to happen, we need to know what the normal sequence is or what the reference is. So we have filled a reference genome sequence which is a common representation, which is not complete in any regards. Doctor Cresco just alluded to that in a more recent study. There was african american population where 10% of the genome was new. That was not a part of the reference. This is just because we have not sequenced enough individuals of different ethnicities. So the reference genome is not complete in any regards, but it does serve our needs to a certain extent. So that's what the reference human genome is, that we use it to see through the different variations and look for variations that might be causal. To give you the context. The first human genome was sequenced back in 2003. It was a huge effort on part of several institutions. It took 13 years to complete. The cost was enormous just to sequence one human genome. It was around $3 billion. Now, we can sequence the entire genome of a person in few hundred dollars. So that's the progress that we have made through these years, and that's the progress that has happened in genetics and clinical genetics. Now, if I were to say that we sequenced the entire human genome in 2003, that would be a false statement, because we only sequenced around 90% to 92% of the human genome. That's because of the technical limitations. They were difficult to map regions, difficult to sequence regions in the human genome, and we could not reach 100%. More recently, we used a consortium called Telomere to telomere consortium that made the human genome sequence more complete. Again, we did not reach 100% of the genomic content. That is because in that consortium, the Y chromosome was not sequenced. But more recently, the Y chromosome has also been sequenced to a certain extent. So we are very close to a complete genome sequence. But again, it would be inaccurate to say that we have sequenced the complete genome just because of the diversity that we have in the world. And we would need to sequence individuals from different ethnicities so as to make a more comprehensive reference genome against which we can look for causal variance.
[00:35:36] Speaker A: You talked a little bit about optical genome mapping, and this is such an exciting topic and an exciting development in the world of laboratory genetics. Can you tell us more about this test?
[00:35:47] Speaker C: Yeah. So, optical genome mapping is a next generation technology we refer to as a next generation cytogenomic technology, and you can compare this to next generation sequencing. So a decade ago, we were doing sanger sequencing, pyrosequencing, very low throughput sequencing technologies were used, and then we had this next generation sequencing technology, or massively parallel sequencing, which is very high throughput, and we could sequence to this day the entire human genome. So the cytogenetic field was lagging, if I can say that it was lagging with respect to a high throughput method, which would have a higher resolution than what we are using right now. In the cytogenetics lab, we commonly use three different methods, karyotyping, fish and chromosomal microarray, to identify different classes of structural variations. But even with the use of three different methods, our resolution is limited. So what optical genome mapping provides us is it gives us an opportunity to identify the different classes of structural variations which would be identified with these three different methods. So it ideally replaces the three different methods that are used in a lab, and it also provides a higher resolution to identify these sp's that are picked up by these different technologies. We were just referring to the cost and the time to reach diagnosis. One of the reasons for that is that we have to use multiple tests. It's more of a rule out approach, that we rule out a certain variant type, and then we move out to a different test and rule out another type, and so on and so forth. So what this test would provide us is, since it's a single test that can identify different classes of structural variations, we would identify these different classes in a single test. So that reduces our cost, but even more importantly, it reduces the time to reach a diagnosis. So that's one clear advantage that I see of using the technology. Apart from combining these different methodologies, there's even a rare set of disorders called repeat expansion and contraction disorders, which are very specific disorders for which there are very specific tests. So one test just looks for a specific repeat in a specific gene. So one test for one disorder. What this technology provides us is it gives us an opportunity to do a genome wide survey of all these different repeat, expansion and contraction disorders in a single test. So we can do a genome wide screen and look for different repeat expansion and contractions with a single test and with a single analysis, which is a huge technological advancement in our field of clinical genetics.
[00:38:33] Speaker A: That is fantastic. And that leads me to, as we wrap up, what does the future look like for genetic testing?
[00:38:41] Speaker C: Our hope is that we will be able to increase the diagnostic yield. That is, that we would be able to provide answers to more patients and more families, upwards of the 40% that we just referred to. Our hope is also that we would limit the time to reach a diagnosis. There's a common terminology which we refer to as diagnostic odyssey. So Doctor Koresco referred earlier that the time to reach a diagnosis is on an average, five years, which I think is a huge time. If you think if you are affected by a condition and you just do not have an answer, it's criminal in that regard, that you cannot reach to an answer, and then the steps that would lead from there on. So I think increasing the diagnostic yield and ending diagnostic odyssey is what we strive for, and I hope that we would accomplish these two feats in the next decade.
[00:39:37] Speaker B: So we were talking about how long it took to sequence the first human genome, which was more than a decade, and how much it cost, which was close to $3 billion, and how now it costs $300 to sequence the human genome. And Doctor Sahaj pal, how long does it take to sequence the human genome?
[00:39:56] Speaker C: Now, on the lab part, it takes around two to three days at max to sequence a human genome.
[00:40:03] Speaker B: So my hope is that that trend continues, that our testing technology has faster and faster turnaround times, that the cost continues to decrease significantly, and also that as a field, we're able to do more where it comes to health policy, so that maybe when a first year test is recommended by the ACMG, that it doesn't take eleven years for health insurances to extend coverage for it. Those are my hopes.
[00:40:32] Speaker A: This has been a really fascinating topic and I really thank you both for being here.
[00:40:37] Speaker B: Thank you so much, Jan. It was great to be here. And I want to say a big thank you to Doctor Sahash Pal for giving us his very valuable time.
[00:40:46] Speaker C: Thank you so much for having me and it was very nice talking to you both and discussing these very key points that are very critical to lot of people out there. Thank you.
[00:40:56] Speaker A: You will find more information about research and genetics on our
[email protected] dot. You can also access clinical Pathways on the Health Professionals section of the website. And while you're there, sign up for our Doctalk newsletter. Want more Doc Talk? Get our latest episodes delivered directly to your inbox when you subscribe to our Cook Children's Doctalk podcast from your favorite podcast provider. And thank you for listening.
