 So are you ready now? Yes, please. Good. OK. Well, I want to thank you for inviting me to do this. And I also wanted to point out that I'm doing this not only as the medical director of the American College of Medical Genetics and Genomics, but also on behalf of the Inter-Society Coordinating Committee that Dr. Bob Wilden heads at DNIH. And it actually was his idea to start this series of talks. Today I'm going to talk about understanding genetic tests and how they're used. And I'm doing this from the perspective of a clinical geneticist, which I was for 29 years at the Medical College of Georgia in Augusta, Georgia prior to starting this job with the American College of Medical Genetics and Genomics. And I just wanted to start and sort of just remind people that genes are made of DNA and they're carried on chromosomes. In the day, people used to say that every specialty had its organ and that genetic's organ was the chromosome. But now we've gotten into much more detail in chromosomes. We'll talk about that. And can I go back to that? Number three, it sort of hops. There we go. I just want to point out the genetic disorders as a result of alterations in genetic material. And as you can see in the picture, the types of changes can be a break of a chromosome or an extra piece of a chromosome. A change in a single base in a DNA code of a gene or there could be expansions. And we'll talk about these. The other thing is just because something is genetic does not mean it's inherited. There certainly are many genetic diseases where the gene change has happened spontaneously, potentially in the course of prior to conception or in the case of cancers, something that's acquired during a person's lifespan. So today I'm going to talk about the types of genetic tests that are available, what the tests entail, what the different tests can detect, and then how to decide which tests were tests or appropriate for a genetic given clinical situation. Okay, let's go to number five. And we talked about genetic tests. You can talk about chromosome tests, which are called cytogenetic tests. We talked about DNA tests or something that's called molecular tests. And then there are biochemical tests for various metabolic disorders. And we're going to talk about cytogenetic and molecular tests today. Okay, where did it go? It is where ours is, it says meeting password. Excuse me. The presentation is more about... What is the meeting password? Genetics. Genetics. Should I pause here? Please, a minute, Dr. Flannery. Okay. Looks like somebody else took over the screen. It's not responding. I'm getting that fixed, give me a minute. Okay. Should we maybe let Dr. Rosenberg know that we can see his messages? Yeah. Probably so. Alan, we can see your messages. I hear you Claudia, thank you. I'm not sure how or why that's happened. I shouldn't have anything on your screen. So it's amazing. Alan, you're sharing your screen. How did I share my screen with all of you? No, but you did. What is the meeting password? I clicked at the top where it says types of genetic testing and your slide deck came up. There was a tab for Alan Rosenberg and one for meeting info and quick start. I hope my message has gone away. It has. It wasn't too scandalous. I wasn't saying, it was, it's public information that I'd present at the U.S. services thing. I was just afraid you were going to go further. I was going to make a smart remark to Beth who, since Accenture wanted to know who it was, that it was okay, but I'd tell them I only charged 10,000 an hour for consulting fees. But, oh no, that's Accenture who charges that. I was kidding. Okay, so now I have control again. Yes. What is the meeting password, Connecticut? Right, so chromosome testing was looking at chromosomes that other name for it is karyotype. And as you can see here, this is the result of a karyotype. And normally chromosomes come in pairs and typically people have 23 pairs of chromosomes. Chromosomes are typically shown this way from largest to smallest with the sex chromosomes over separately. Chromosome abnormalities can include having an extra chromosome like this extra chromosome 21 here which produces a genetic imbalance of the genes on that chromosome and produces Down syndrome. What you're probably unfamiliar with is how chromosome tests are done. What happens is blood is drawn. It is typically in a anticoagulant, usually heparin. And then the blood is cultured with phytohemagglutinin and they are stimulated in culture typically for three days, although they can be done for a little bit shorter than that. They then add Colchicine in hypotonic saline and this then enables them to spread out the cells on the slide. They then digest the chromosome, so they remove all the proteins and then they stain it and they look at it under the microscope and then take the visual image and sort out the chromosomes to make that neat karyotype. So this is labor intensive and takes time. And typically we use karyotypes to diagnose conditions such as Down syndrome. And even though you may feel kind of a child has Down syndrome looking at them as a genesis, you still would do a karyotype first to confirm that indeed the child has Down syndrome, but secondly to determine if it's due to what we call trisomy, where there's three separate chromosomes or what there's due to what's called a translocation producing trisomy, in which case there's up to 50% risk that it's inherited from a parent who has rearrangement of their chromosomes so it's called a balanced translocation which would impact the recurrence risk. So karyotype can detect whether there are too many or too few chromosomes, whether it's a missing part of a chromosome which means they then have only one copy of the genes for that region of the chromosome. So when duplication, so in which case you would have extra copies of genes and then translocations which I just mentioned have pieces of chromosomes that are broken and reattached to each other. Excuse me, Dr. Flanery, can people remember to put their phone on mute please? We're getting some background noise. Thank you very much. Karytyping has its limits because many deletions or duplications that are clinically significant are not visible even under the microscope and we commonly call those micro deletions or micro duplications. And we can detect these by using what's called a FISH test which stands for fluorescence in situ hybridization. And what FISH test involves is taking a probe which is single-stranded DNA that has fluorescent molecules attached to us and depending on what chromosome and what reason of a chromosome you're trying to look at with the FISH probe it would match up with a particular color of genes in that region. And as you can see here it's applied to the chromosome and it attaches where the complementary region is. Now what can happen is, as we see in the next slide if we can get there, there are some conditions such as one called DeGeorge syndrome in which what happens is you have using this probe specific to the DeGeorge critical region you see that in one chromosome 22 that region is present because the probe could attach and this other 22 it could not attach because that region is missing so there is an invisible to the naked eye and into the microscope micro deletion in that region of that chromosome but the FISH test demonstrates that region is missing. And there are other micro deletion syndromes and one or more common one is Prada-Willie in our Angelman Center and we'll talk about that subsequently and under duplications that can be detected in one form of Charcot-Marie-Tooth disease they actually can use these DNA probe here for this region of this gene and they look for duplications or extra copies of the genetic material there which confirms that form of Charcot-Marie-Tooth. A very rare disease that you've probably never heard of and I'm probably mispronouncing because I've never seen a case called Thalysius-Mertzbacher, there's a duplication of a particular region. Now another use of FISH is for rapid diagnosis of trisomies and for example, if we have a newborn in a neonatal intensive care unit who has severe congenital heart disease and physical abnormalities, one might be concerned that the child may have a condition called trisomy 18. And trisomy 18 is very severe. The chance of survival to age one is very small despite aggressive medical care and cardiac surgery in this setting would be potentially very risky for that child. A karyotype takes 72 hours but using interface FISH where they take the cells and they deposit onto them these FISH probes. They can sit there and look and detect in this case here that there are three signals for chromosome 18 in these white blood cells, confirming that the child indeed does have trisomy 18. This test takes a few hours to get results rather than days so it can be extremely useful in this setting and help parents and physicians have informed discussions to make decisions. So now we're gonna move on and talk about a patient who needs genetic testing. We'll talk about how we make decisions about testing and then what tests would be indicated. So we have a hypothetical patient, a boy who has microcephaly, hyperactivity, seizures, developmental delay, verbal apraxia which typically is manifested that they have a very limited vocabulary, say five, six, seven, eight words total and a very happy effect in this patient. So the doctors concerned the child may have Angelman syndrome. Now we know that 68% or so of cases have a microdillusion of a region of chromosome 15. So the first logical step in valuing this child for Angelman syndrome would be to order a FISH test with a specific DNA probe that detects this region of chromosome 15. So here tests have been done and the result is that no deletion was detected in the Angelman syndrome critical region and the next step is, well, we're still concerned it's Angelman syndrome, we don't know how to manage this patient. So we go and we just look into 11% of cases are caused by mutation in the UBE3A gene. 7% have uniprotodisomy, three have what's called an imprinting center defect and then a smaller number have other abnormalities. So logically the next step would be to do the UBE3A gene sequencing. This is probably a little schematic for you but this is explaining the process of how they do gene sequencing and it's become automated in machines now where they can put in the DNA after amplifying the region of the genome that is targeted for the testing and then the machine basically goes through and is breaking up the gene and looking at what the pieces of the gene are and it then generates a diagram like this which is showing you what the code is going along a segment of the gene. And here we have results of sequencing the UBE3A gene and a patient who has abnormality in the UBE3 gene and it's showing that the patient has a change at this point in the gene which is not the normal base that should be in that region so therefore it's a mutation that is causing the problem. Now sequencing results can be complicated because there can be changes in the gene and you have to determine whether they cause a problem or not. American College of Medical Genetics and Genomics and the Association for Molecular Pathology put out a joint policy statement this year establishing standards and guidelines for the interpretation of what we call sequence variants because a change in the code could simply be a variant or it could be causing a problem. It's we establish standards for how you would interpret whether a change is what we call pathogenic which means we feel confident that it causes the gene to malfunction. Likely pathogenic which means it's most likely does cause malfunction. Benign which means a change in the gene produces no effect on how the gene functions or likely benign and then of course unfortunately at times it's of uncertain significance and for the physician and the family and I'm sure for the payer getting to that point the result comes back of uncertain significance can be a bit of a challenge. Now sometimes we'll have a false negative test result. So you do the test you don't find a change in the gene. Well the patient may have a change in the gene that you tested but there's another gene that's also responsible for producing what we call the same phenotype which is the abnormalities in the body or behavior or combination of those two. They could have a sequence change that cannot be detected by sequence analysis which includes what we call a large deletion and frequently if you know a gene is prone to have deletions when you do a sequencing test you may then if it's negative reflects to doing a fish probe for looking for deletion. And then sometimes the test would be negative and the patient has a sequence change in a region of the gene that's not covered by the test because not all regions of all genes are adequately sequenced and covered. And this especially applies to whole genome and whole exome sequencing which will be I think a topic of two talks later. So now another useful test that we call a chromosome microarray test I know you've all heard about this. Typically it's called a gene chip that uses comparative genomic hybridization to look missing regions or extra segments of regions of chromosomes. And the easy way to think about it is it is performing thousands of fish tests simultaneously and I'll show you. So this is from a now defunct laboratory called Signature Genomics but it was in their educational material that they had. So basically what they do is using the same kind of microprocessing technology they use to make a silicon, you know, computer chip. They can actually put tiny pieces of gene sequences onto these silicon chips or glass chips. And you can then know which one are there. And so what they do is they put probes that are attached to this chip that are unique segments of every chromosome. It's a depending on the number of probes that can represent every genetic reason of the entire genome. And that's pretty much what chromosome microarrays are like currently. So here's the chip. Here's the probes attached to the chip. You then take the patient's DNA and you take it so that you heat it so that the DNA separates from being double stranded and to be single stranded. And then these pieces are put into the machine in the chip and they all sort of up and pair up with their areas that they match up to. And so here though, you have a case where the patient's DNA doesn't attach to this probe. And so there's not a match for that area. And they have now computer processing that analyzes the entire chip and it comes up and it gives you a report that tells you if you've got duplicated genomic material from a particular region or multiple regions or a deleted genomic region. And sometimes you'll find multiple deletions or duplications simultaneously, although that's not as common. Now, the microarray can tell you if there's a duplication or deletion, but it can't tell you if it's been caused by a rearrangement of a chromosome. So sometimes having done a chromosome microarray then leads to the need to do the old fashioned chromosome test, which is sort of counterintuitive, I'm sure to many people, but it can be a necessary next step in evaluation. Microarray results make 10 to 15% more diagnoses than karyotyping and the evaluation of patients with idiopathic learning disabilities. Some microarrays have been reported as having as high as 28% rate of diagnosis. And ACMG put out a practice guideline in 2010, affirming the use of chromosome microarray as a first tier genetic test and evaluating patients with intellectual disability under a multiple congenital anomalies. And just recently, the European Journal of Human Genetics published a report talking about the clinical utility of genomic testing and particularly looking at what subsequent medical recommendations came about in patients after they had a microarray test done that showed an abnormality. And in some instances, this would have to do with management of the patient such as doing further testing, knowing there's a high incidence say of seizures and having a patient evaluated for that or the child may have an increased risk of developing cancer down the line, the sort of surveillance for whatever type of tumor that might be would be indicated and other sorts of investigations that would be indicated. Just like with doing sequencing of genes, a microarray test may come with a result that they say is normal or say it's pathogenic, likely pathogenic, likely benign, a variant of unknown significance. And when you have a variant of significance, the lab frequently recommends testing the parent to see if either of them has the same change in the gene because if either parent has the same change in the gene and that parent is healthy and normal, then that change is not pathogenic. Conversely, if the parent's for testing either has that same change, it's not possible to say for sure whether the change in the child is causing the child's problems, although you would be suspicious of that. Now, someone had asked about SNPs and so we tried to talk about what was called STIP arrays. And they are microarrays that have what we call single nucleotide polymorphisms in them. What a single nucleotide polymorphism is the variation of a single base pair of the DNA sequence from the typical. And so here's a picture diagram of what a SNP is. So here, at this one location in this gene sequence, this individual has this sequence. At that point, this individual has this base. SNPs do not necessarily change the function of a gene and typically they don't. That's why they're called single nucleotide polymorphisms because a polymorphism doesn't have functional effects. As of the last time I checked, SNP arrays have 1.8 million probes for SNPs and they have different ones they use. And if the test in the individual is tested has a specific SNP in a specific gene that's called a positive result. It can also detect small deletions or duplications. But what's really interesting is doing the SNP arrays can yield surprising information beyond that. It's called loss of what we call heterozygosity. And so it was first called to Genesis attention in an article in Lancet in 2011 which called attention to the fact that they could identify incestuous paternal relationship by SNP array. And what they found in this article was that these green regions of these various chromosomes had two copies of the same rare SNP. And this degree of what we call homozygosity is best explained by the parents being related to each other and passing down SNPs that they carried by being related to each other. And this actually does come up. We had an internationally adopted girl who had mental retardation, non-specific abnormal facial appearance. And since she'd been adopted internationally there's no family or prenatal history available and her parents had been trying to find what was the cause for a problem to figure out what could be done for her more specifically. And she'd had all these tests done before she came to see us. And so SNP arrays were available and we said, well, you know, let's take a look at this. Well, this girl had a very high degree of homozygosity of regions of her chromosomes. It would correspond to the biologic parents being very closely related, like closer than first cousins. And so it led us to be concerned that she might have some sort of autosomal recessive disorder because she could have received two identical copies of an abnormal gene from her related parents that we didn't have a clue as to what that might have been. And that was back in 2012. Here we have another patient we saw back in Georgia. And this girl had a very complex phenotype with metal retardation, non-specific dysmorphism. So she was unusual looking, but not characteristic of any particular appearance. She had multiple congenital anomalies and she had endocrine dysfunction. And so we did a SNP array on her and one of the regions with homozygosity was that had contained the gene for Bardet-Biedel syndrome type seven. And she had features compatible with this condition, but she lacked many of the characteristic features. And so what we decided to do was go and try to get sequencing for that specific gene done on her. Unfortunately, she had managed care Medicaid and it did not get approved. And I'm not sure what's happened with her since that time. All right, now we're gonna talk about another patient situation. A three-year-old boy who's not walking and has only a few word vocabulary. His growth is normal. He has a long facial profile. Family history is not significant. And so it would be the first test to evaluate him. Well, as I mentioned, ACMG practice guidelines had recommended chromosome microarray in this setting as the first-year test. So of course that was done and is normal. So you go, what's next? I mean, what tests do you order? It has to be some logic to this. Well, the most common cause of intellectual disability in males is something called fragile X syndrome. So the physician sends blood for fragile X testing. And this comes back and showed, gosh, I have something out of secret time. It was expansion of the fragile X gene. This is showing that it's what we call a CGG repeat. And Dr. Jack Tarleton gave me these slides that shows you that normally people have 29 or 30 of these three base pair repeats in that gene. When you have significantly increased number of repeats, you end up with dysfunction of the gene, which produces them, we call the fragile X syndrome. This is showing another way they do it, which what they used to call Southern Blot testing. And it actually was a more tedious process than the previous one they were showing when we call PCR testing. And it actually used radioactive labeling to be able to show where the region that you're concerned about is and the size of this corresponds to the number of repeats. So our patient had 330 repeats, and so had fragile X. The mom needed to be tested because the risk of having another affected male increases depending on how many repeats she has. So depending on the number of repeats that the mom has found to have, affects whether or not there's a greater than 50% risk of another male happiness condition or a lower risk of it happening. In addition, women who have expansions of the gene are at increased risk of developing premature ovarian failure and should be monitored for that. And then it was most interesting about this and something that we've only learned over time is that her father should be offered testing. I put should be tested, but he should be offered testing because he could have, we call it pre-mutation expansion of that gene, which places him at risk for developing what's called fragile X associated tremor, ataxia syndrome as he gets older. And knowing that he has that would certainly make it much easier for neurologists to diagnose why he's developing a tremor rather than start worrying about doing all kinds of tests for all kinds of other potential neurologic disorders to produce tremors. There are many other tri-nucleotide repeat disorders. You've all heard of Huntington disease. There are a whole host of spinal cerebellary taxias that have tri-nucleotide repeats. And there's a condition called myotonic dystrophy which is produced by tri-nucleotide repeats. And we've reached the end there. I think we've given people enough time for questions as well. Great, Dr. Flannery, thank you very much. We really appreciate you taking the time to speak with us today. At this time, I'd like to see if there are any questions from anyone on the line for Dr. Flannery. Well, Dr. Flannery, I have a question for you while we're waiting to see if anyone else from the audience has a question. I'm wondering if you could address that if the types of mutations that are detected by fish can also be detected by CMA, why would you choose one type of testing over the other? Right, well, in the case, say, for Angelman syndrome, the patient's phenotype is such that you feel very concerned that as Angelman syndrome, doing a fish test would be probably less expensive than doing a chromosome microarray test. You're correct, a microarray would be able to detect that region, at least most microarrays would have probes for that region, but that depends on how confident the physician is. A pediatrician who's concerned about the child might very well do the chromosome microarray, whereas an experienced medical geneticist would see the patient and be concerned specifically about Angelman syndrome and then be doing that test. It has to do with the people seeing the patient and their experience. Great, thank you. So I have another question, but I'm gonna see if there are others out there with a question first. So with our webinars, people type in questions, but I don't see where you have that here. Yeah, this is Dr. John Goldenring, Pediatric Medical Director out in California. Can you hear me? Yes. I wonder if you'd review a little bit more for us about the utility of the microarray testing and particularly if you'd address the issue of kids who have autism. What is the clinical utility of finding micro deletions in kids who have autism? Right. Do you want me to talk about the clinical utility? Well, I mean, you showed that article, which I'll go get from Europe, which goes over a lot of stuff, but I want to focus particularly on the autism thing. I think we see the largest number of microarrays requests may be coming from all these kids in our epidemic of autism, and I, as a pediatrician, haven't found any good literature that says this is clinically useful at this time, and I will qualify my statement because there may be something that we discover over time, but at this time, we don't know what that means. Why would you do this? Right. There are other articles besides that one from Europe about changes in management of patients after chromosome microarray testing, including after dealing with them for children with autism. And it has to do with what region is found to be abnormal and then what other medical issues could result from that. And most often, it would be there's an increased risk for having some other medical problems such as renal abnormalities or some other problem in terms of neurologic function or risk of congenital heart disease that was not necessarily going to be obvious. I can try to track those down for you and send them to... I think that's actually fascinating. If indeed, we got back reports as pediatricians that said, because this particular area is involved here, we think there's a higher risk of X, and that's not something I've seen a lot of, I might find that fascinating, and it would be interesting to see if that could be quantified. And yes, I think many of us would appreciate... Sure, okay. I'll try to find some other articles as well. And just my personal experience, I've had the experience of having a child who would do the testing, and it came back with a micro deletion in a particular region, and among the genes in that region were one that was associated with, I forget what type of cancer. And so it's like, what do we do with this? Something took a pediatric team of colleges, oncologists, and they've had to then figure out how you would evaluate the child and monitor them for development of that particular tumor. And that's what I specifically remember. And then I do remember a patient where in that region that was involved in the child, that there was the increased risk of having either, I think it was a renal malformation or it was renal agenesis. And so that led to doing ultrasound of the kid's kidneys, which were fine, but I suppose we found out he only had one kidney that could have some significant implications for his life. But I'll be happy to try to find those other articles for you as well. It was just fortuitous that one from Europe happened to just pop up in my email when I was working on putting this talk together. And it was like hot off the press, so I figured that was a good one. Thank you, that would be helpful. And by the way, it's a superb summary talk. Thank you. Thank you. Dr. Ponnery, a follow-up I think to the last question and that you're the article from Europe that you referenced about. I think the percentage of patients tested who had a positive finding. The question I have is who exactly was being tested in that study. I mean, is it anyone with any sort of intellectual delay or is it particular types of intellectual delays coupled with perhaps other phenotypes, other findings? This is being recorded, of course. Here I am scrolling back through the slides. Probably gonna cause somebody to have a seizure going this fast. It's fine. Can't read this, 752 children with congenital anomalies and toward developmental delay who went chromosome microarray testing. That was their target group there. That doesn't mention autism in that group there, but children with congenital anomalies or developmental delay. And typically, my recommendation is that the child just has autism and doesn't have developmental delay. I think it's unlikely that a microarray is gonna identify much of anything, to be honest with you. That's just my personal opinion. That's not the opinion of the American College of Medical Genetics nor necessarily everybody's opinion. Dr. Flaner, this is Megan McCarvillian with the Association. It was a very nice presentation. I wish I'd had this like two years ago when I'd started trying to write policies about microarrays, but I'm curious about how much practitioners need to consider differences in the composition of the microarrays. My understanding is that what you test for is dependent on what it's looking for, but I don't have a good sense for how you know or how a practitioner would know what you need to be looking for. Yeah, I mean, what you're bringing up is that some labs have their own particular microarray and they have their own particular probes that they use in their microarray, and it can differ from lab to lab. I know that ACMG has technical guidelines for laboratories. It has like standards for this, and that hopefully is becoming more adopted or cross-thing, but in many instances, these are something that's not, it's sort of more like what we call an LDT sort of test. I've actually developed tests as opposed to a standard thing that's purchased, so though I think it's probably going towards becoming more standardized as things go along. But certainly, I know there are labs that have their own particular microarray that they have adopted and used, and in some instances, I guess they consider it to be a proprietary unique product that they've chosen certain genetic regions and the depth of coverage of certain genetic regions is being more important. At one point in time, I think there was like sharing of data among labs, and I'm not sure what the status of that is for them to help interpret what becomes useful and what isn't, and then also to help people learn what might not be a variant of unknown significance anymore. They help them determine that it's not pathogenic or it is pathogenic, and I'm not sure what's happened to that. I was thinking this, Dr. David Ledbetter was involved with that in this driving that sort of process, but I'm not sure what's happened since he moved to another institution, but you're correct, and it would be, by now, I think it's getting more standardized, but I know there still are proprietary microarrays out there. I'm not gonna say who I think has the best microarray, but I would think that if they're, at least adopting the technical standards that ACMGs, expert review and evidence-based review process, they'll recommend what the critical elements for a microarray should include, and that should be pretty reliable and appropriate to use. Great, thank you. This is Alan Rosenberg, and in fact, the funder thanks a lot to the presentation, as the others have said. I lead medical policy for Anthem, and it's funds, including Blue Cross Blue Shield of Georgia. So my question is an extension of the clinical utility process earlier, but it's to the asymptomatic individual, just one of the cases you cited is an individual where you recommended it might prevent the future workup. If the father or grandfather, rather, at age, they develop an ataxiocendrome. My question is why in the asymptomatic individual would you do that, rather than simply share that possibility and wait to see if they develop an ataxiocendrome and do the testing at that time in terms of clinical utility? Well, as I phrased at the slide, I didn't put in with how will you do it as a practitioner or clinical geneticist. You would discuss it with the grandfather and say, we know that your daughter has been tested and she has an expansion of this gene. It's very likely that she inherited that from you, and there are problems that can result from you having expansion of this gene and explain what the fragile X-associated tremoratexia syndrome is and the typical signs and symptoms of onset. And we never just tell people they should have tests. We explain to them what the benefits might be, what the pros and cons might be and what people make decisions. And so, in that setting, the grandfather might say, right, I certainly want to know, who knows? But he might say, no, I don't want to know. And they make their decision. Now, the benefit to him of knowing that he has an expansion that places him at risk for developing fragile X-associated tremoratexia syndrome is not gonna come today, tomorrow, next year. But as I pointed out, it potentially can prevent the so-called diagnostic odyssey that we talked about of people being tested for things and trying to find underlying causes, symptoms that are not very specific. But certainly, I mean, the gentleman in question might say, well, thank you, so if I ever develop any symptoms, I'll tell the neurologist I have this risk and then they can do the test then and we'd say, fine. Sounds like you understood everything we told you very well. Excellent, just, you're in charge. I appreciate it. I just been wondering if 50% of people will be tested with a negative right after result and 50% with a positive. Why you would waste the resources today rather than waiting until that time? And even then, I wonder, but it's fine. I just was curious at that point. So I would say, sure. There's my humanities and contemporary civilization traveling with Columbia. Okay, all right. We're good. And maybe I'll send you also a copy of ACMG's recently published policy or bi-sacrifice position statement regarding looking at clinical utility of genetic testing beyond simply, you know, the benefit directly to the patient. Guys, which I sort of touched on here, but you may find that to be a useful report to look at as well. So I'll send that with all of some other papers about clinical utility of chromosome microarray testing. Thank you. Dr. Flannery, we certainly would appreciate that and we'll ensure that all of the participants on today's webinar are able to get access to those materials. Great. Are there any other questions before we say a final thank you to Dr. Flannery today? Great, well, David, we really do appreciate it. I thank you very much. To everyone on the phone, our next webinar is scheduled for Tuesday, October 13th. And on that webinar, we will focus on understanding CPT coding of genetic tests. So we all hope that you can join us then. Thank you very much and have a nice rest of your day. Bye-bye. Thank you, bye.