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#153 - [Tech Tuesday] - 🔬 GeneDx





Hello Everybody 👋

We have a new episode of Tech Tuesday for you today. This month we feature a company called GeneDx that provides rapid exome and genome sequencing.


You can find out more about Gene Dx at: https://www.genedx.com/nicu/


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The transcript for today's episode can be found below:

[00:00:00] Ben: Hello everybody. Welcome back to the incubator podcast. It is Tuesday. We have an episode of tech Tuesday ready for you. Daphna, how are you this morning?


[00:00:09] Daphna: I'm doing great. We've, we've had a busy summer, but we, we've had the opportunity to really get a lot of Tech Tuesdays off the ground, so we, we will continue with our excellent set.


[00:00:22] Ben: we are very excited today. Um to have um, Dr. Paul kruska on the podcast with us today. He is the chief medical officer for a company called gene dx Paul kruska is a board certified clinical geneticist and prior to working at gene dx.


[00:00:42] Ben: Um Paul spent, uh, quite some time at the National Institutes of Health conducting genomic research and taking care of individuals with rare genetic disease. Paul, thank you so much for making time today and be, and to


[00:00:54] Ben: be with us on the show.


[00:00:55] Paul: Ben and Daphna, um, I love your, your podcast and, uh, [00:01:00] thanks for having me.


[00:01:02] Ben: No, pleasure is all ours. And I guess, um, I think the, the, the branding of the company GeneDx is quite good. So you, you hear GeneDx and you're like, I'm assuming they're doing something with genetics and they have a geneticist on. So, so genetics seems to be the field, but, but for people who have never heard, uh, of the company, can you give us.


[00:01:20] Ben: A few sentences or a few minutes of what is gndx? What do you guys do? To bring everybody


[00:01:25] Ben: up to


[00:01:26] Paul: Yeah, um, Ben, the name, the name kind of tells it all, right? GeneDx. So we look at your genes and hopefully give you a


[00:01:33] Paul: diagnosis. Um, we're a genetic testing company. We spun out of the NIH about 20 years ago. 23 years ago, actually. And, um, through time, we've progressed with with technology started out with PCR based single gene test and went to microarrays and panels.


[00:01:53] Paul: And now what we really focused on is doing broad testing for rare genetic [00:02:00] diseases using. Um, next generation sequencing. So that's exome sequencing, and now genome sequencing is starting to come to light. And that's a lot of what we're going to talk about today is genome sequencing, um, in the NICU. So, as you mentioned before we got on the air, Ben, we've certainly stood the test of time.


[00:02:20] Paul: They've been around a lot and really have a great crew, a lot of experience in have accumulated a ton of data, which is really, which is really a lot of fun to work with. As someone coming from NIH, uh, having been a physician scientist in my previous life.


[00:02:41] Ben: And so, um, when we're talking about genetic testing, um, what What exactly do you guys do in terms of we know that there's many ways to send genetic tests There are multitude. There's there's a multitude of genetic tests available. Um, what kind of tests you guys,


[00:02:59] Ben: [00:03:00] uh, Are


[00:03:00] Paul: Yeah, like I said, we, we specialize in whole exome sequencing, whole genome sequencing testing. We also provide other tests. We provide microarray and panels, but really the industry And the field of genomics is moving more towards a broad, a broader base testing because there's just so many different diseases out there and panels and other types of testing are limited.


[00:03:26] Paul: So we're trying to promote testing that has the highest chance of giving the patient an answer and a chance for a precision therapy. So what we do. is we can either take blood or even a buccal swab. About 70 percent of our samples now are buccal swabs where you, you scrape the inside of the mouth of the child or yourself and then you send it to our laboratory.


[00:03:52] Paul: Um, the other, um, 30 percent is usually blood samples. And so these samples come [00:04:00] into our, our lab and what we do is we... We extract the DNA from the samples. We do thousands of these tests a week. Um, and for the exome and genome test, what we do is we break the DNA into little pieces and we massively parallel sequence all of your, your genes.


[00:04:21] Paul: And let's start with genome sequencing first. So we, we, we sequence all three billion. Um, paste, uh, um, pieces of your DNA. So your entire genetic code. And after we sequence that, then we try to find meaning in that. And sometimes it's like trying to find a needle in a haystack. Um, fortunately we've been doing this for a long time.


[00:04:46] Paul: Um, we've got algorithms, we have expert, um, PhDs on, on staff. And about 30 percent of the time we give. are, are, um, patients a, a genetic [00:05:00] diagnosis. Now, um, traditionally, or over the last few years, exome has been more popular. So I, I just talked about genome, that's all of, that's your entire genetic code.


[00:05:11] Paul: Exome is just the protein coding region. And so that's about 1 to 2 percent of your genome. Historically, that's been cheaper, and so it's, the, the payers have gone for that, so we've really focused on that. Currently, much of our core business is still exome, so we are seeing moves to switch over to genome, especially in the NICU.


[00:05:32] Paul: Most of the studies conducted to date have used whole, whole genome sequencing, so the entire, um, the entire genome. And, you know, I, I think this might be a good place just to stop and, and talk about Florida. I know, I know Ben and Daphna, you're both in Florida. And, um, I want to congratulate, first of all, the state of Florida because, uh, there was a recent bill that Medicaid now covers, [00:06:00] um, rapid sequencing in Florida.


[00:06:02] Paul: And this is going to be outside the DRG or Diagnosis Related Group, so Florida joins one of eight other states, so Florida is a progressive state. And, um, a lot of it has to do with a, a, a project that was, Um, done in, in your state called, um, Project Baby Manatee that we, we can talk about more. I don't know if I'm, I'm kind of going off on a side tangent here, but, um, Project, um, Baby Manatee is an example where, where the researchers use whole genome sequencing in the NICU for critically ill infants.


[00:06:36] Paul: So, um, so anyways. In general, at GeneDx, we like to do broad tests, exome and genome tests. Tests that have the highest diagnostic yield, the highest chance of bringing a diagnosis to the individual. Now, there's other types of testing that we do and other commercial laboratories do as well. And these tests [00:07:00] are lower yield and we're trying to get away from it.


[00:07:03] Paul: One of the common ones that I'm sure you've heard of is chromosomal microarray. And this has been around for a long time. Um, certainly, uh, clinicians are used to this test, comfortable with this test, but the diagnostic yield is much lower. And this is looking for big chunks of DNA. Um, millions of base pairs missing, such as 22Q11 deletion syndrome, where you have millions of base pairs missing.


[00:07:30] Paul: This syndrome used to be known as DeJordes syndrome. It's a common syndrome obviously seen in the NICU, um, especially amongst, um, infants with congenital heart malformations. And so the the test I'm talking about called genome sequencing and the NICU, that would cover everything that a microarray would do, but much more. That was a very long winded


[00:07:55] Daphna: Can you tell us a little bit? No, it was great. It was great. It was great. [00:08:00] Tell us a little bit, you know, logistically. Um, you know, we know that there's a handful of babies that we are going to send genetic testing on. But, obviously, in the medical community, there's this thought that maybe genomics will be a part of our, like, routine care of everybody.


[00:08:20] Daphna: Especially... in neonates who we don't know that much about. So what do you think the future of genomic testing


[00:08:27] Daphna: really looks like, especially as it relates to


[00:08:28] Paul: yeah, I love it. Thank you. Thank you for bringing that up. So what you're saying is maybe genome sequencing should be an a consideration for an admissions laboratory. And we think that way. We're doing a project called Seek First out at Seattle Children's. The P. I. Is Mike Banshed. He's a well known geneticist in the field and his co researcher, Tara Wenger.


[00:08:55] Paul: And what we're doing is a genome first type of study in that [00:09:00] NICU where we're sequencing individuals as they come into the NICU before we do anything else. So kind of like an admissions lab. And the criteria, the workflow is really simple. If the infant's medical condition is not fully explained by trauma, infection, or prematurity, so not fully explained, they qualify for whole genome sequencing.


[00:09:24] Paul: And we find that about half of all infants, um, entering the Seattle Children's NICU qualify for this. And of course, we have to qualify that this NICU is a freestanding NICU and it's level 4. But about half of all infants meet that criteria. And then about half the families participate in this study. So we are testing this idea.


[00:09:46] Paul: We've presented some of the data at various conferences and we're working on our first manuscript. So we think this is a good idea. And there's other studies really to support this idea of this that that we don't [00:10:00] really know, um, what's going on. I'm going to go back to seats first for one more moment.


[00:10:06] Paul: Um, we found that when we sequence these infants coming into the NICU, one third of them were not suspected of having a genetic diagnosis. Because remember, we're sequencing them when they come into the NICU. And from the medical records, about a third of these infants do not have genetic consultation. So there's no suspicion.


[00:10:29] Paul: So that's, that's interesting. And, um, We don't, you know, the two of you, Ben and Daphna, you're neonatologists. Sometimes it's hard. It's hard to figure out what is going on with this kid. Um, and there's a recent study that just came out two weeks ago in JAMA, and it was called the Gemini Study. And to this point, if you looked at the pre [00:11:00] test, so this was whole genome sequencing in the NICU compared to panels, actually, we could talk about that more.


[00:11:05] Paul: But if you looked at the pre test differential diagnosis of those clinicians, Only one third of the time with anything on a differential diagnosis matching the molecular diagnosis of the test. So I, I think, Daphna, to your point, it is a good idea to think about genomic testing early. And as an admission lab.


[00:11:30] Paul: Now, we have a long way to go. The reality right now is that in, in the United States, um, genetic testing or rapid genetic testing, which we want to talk about today, um, that's where you get a test back the results back in a week. So it's done really quickly or less than a week. It's rarely done. In NICUs around the nation, there was a recent study that pulled some data from Optum on thousands of children in the [00:12:00] NICU, and in children with one or more identifying features of a genetic condition, genetic testing was only done in 7 percent of those.


[00:12:08] Paul: And so we know that there's, there's, we still have a long way to go before this is widely adopted. Um, and, and, and right now it, it is, the, the truth is that it's not in, in the U. S. We really have a long way to go to promote genetic testing.


[00:12:25] Daphna: You, um, mentioned


[00:12:26] Ben: interesting about everything. Oh, sorry.


[00:12:29] Daphna: ahead, Ben.


[00:12:31] Ben: Go ahead.


[00:12:33] Daphna: Well, you mentioned a few data points that are interesting, but one that I was particularly interested in, as you say, about, you know, 50 percent appearance will move forward with the genetic, uh, testing. You know, I think that's, It's something we all wonder, like, how will the public accept this? What do we do with the information?


[00:12:54] Daphna: Can you tell us a little bit about how that's gone, um, when approaching parents?[00:13:00]


[00:13:03] Paul: Yeah, so, um, I think, I think the information is a good thing. It's going to lead to diagnoses. Um, it's going to lead to precision therapies. Um, it's going to end the diagnostic, the diagnostic odyssey. We know the diagnostic odyssey is, is, is, you know, between five and seven years in the U. S. Um, and I think the concerns about the privacy, I think you're alluding to the privacy and security of this information, my genetic code.


[00:13:33] Paul: Um, I think we have to put that in the same box as all of our information, right? All of our health records, uh, need to be protected. They're going to be, um, in electronic medical records. It's the, the genetic information is just as sensitive as, let's say, your mental health, um, records or, or other sensitive medical records that now is going to be in the cloud [00:14:00] and other things.


[00:14:00] Paul: So, this, this certainly is, is a, is a valid concern of, of many patients and families when they're getting genetic testing. How is this going to be used? Who's, who's going to get their hands on it? So, that, that's, that's definitely a valid concern. I will say that across the board. In the literature, most families are very satisfied and happy that they had genetic testing in the NICU, even when the test is negative.


[00:14:29] Ben: Mhm. And so I think that's, that's, that's a great segue to my next question, which basically I'm putting myself in the shoes of, um, a clinician listening to this episode says, Oh my God, I've sent genetic testing and I get like some, some variants that we don't know where they are. And, and we end up with more questions than answers.


[00:14:47] Ben: But I think one of the things that, sets GeneDx apart and something that I was fascinated by is this idea of of the database that you guys have on all these genes and variants [00:15:00] that allows you to make connections that up until this point we were not really able to to do. Can you tell us a little bit about what that is and how does that help you make, uh, how does that help you on the diagnostic


[00:15:13] Paul: Yeah, so if we've seen the variant before, we know it causes a disease or syndrome or that, you know, that particular variant in a, in a gene. Then we have more confidence in making that call and saying, Hey, this is real. This is something also, we also like to do something called trios. So it's a lot easier if you get both parents and the child, because a lot of the, the variants are called de novo where only the child has the variant.


[00:15:42] Paul: Only the child is sick. So it's a spontaneous mutation in the child. So we also have the parents. In our library and we can look, use the parents as controls and background so we can figure out, wow, this is, this is commonly seen in the population. So [00:16:00] it's less likely to be pathogenic or disease causing.


[00:16:04] Paul: So, yes, we have over 400, 000. Exomes in our database, and that's very helpful. We do share, um, the pathogenic variants in a public database called ClinVar and other commercial laboratories also do that. We also use that database to, to, to make these calls, but certainly our 400, 000 plus exomes is, is very helpful, um, in, in making these, these, these calls.


[00:16:30] Paul: These diagnostic calls. And just one more thing I want to emphasize is the concept of variance of unknown significance. We don't really report a lot of variance of unknown significance. Um, when you're doing a trio, um, you can really narrow it down or you're doing, um, genome sequencing. That's kind of a myth that it's the more, the wider the test, the more variants of unknown significance.


[00:16:59] Paul: Most of our [00:17:00] tests have one or zero variants of unknown significance. Um, and so we, we really only give back information. If it pertains to the, the clinical presentation or what we say in, in, in clinical genetics, the phenotypes, um, we should be saying the clinical presentation in my book. So, um, and I mean, let's break this down, right?


[00:17:24] Paul: I think this is a valid concern, Ben, that, that you're making.[00:18:00] [00:19:00] [00:20:00]


[00:20:22] Ben: Um, okay. So my last question before I, I definitely close out the show is, let's say you're a clinician, you're listening to this and you say, man, these guys have a fast turnaround time. They have this, this amazing database that helps makes diagnoses. Um, people don't even know where those labs are going if they order them.


[00:20:46] Ben: So how do they know how, how can they initiate the process of, of sending, uh, exome sequencing through GeneDx at their


[00:20:52] Paul: Yes. Um, we have a portal so you can do it all online. You go to gdx. com. Um, we [00:21:00] have a portal. You can order the test through the portal. And certainly we have a customer service department that that can walk anyone through this. Um, and. We, we, we feel strongly about customer service and, and, and trying to help people get this test because we, we want patients and families to have access to, to, to a genetic test and a precision diagnosis.


[00:21:25] Paul: So, um, it's not that hard. We walk you through. We also have genetic counselors that can help you with pretest counseling. Um, post test results. So we, one thing we, we want to try to make this as easy as possible to order. There's nothing more frustrating for a clinician to, to be fumbling around, uh, having difficulty ordering the test, um, getting frustrated, um, especially in the NICU.


[00:21:52] Paul: You guys are busy enough, right?


[00:21:56] Ben: On behalf of all clinicians, we thank you for that because yes, we, [00:22:00] the, the shuffling to find how to send a test is, is just the bane of our existence.


[00:22:07] Daphna: Um, Dr. Krushka, my last question is, obviously you're, um, an accomplished physician scientist. Maybe you can speak to the need, um, that we have for clinicians to engage with Industry, which is sometimes, uh, you know, uh, a taboo, so to speak. Um, but, but certainly, uh, you know, it's a mutual benefit of your expertise guiding, um, the industry.


[00:22:35] Daphna: Tell us a little bit about that.


[00:22:37] Paul: I didn't catch all of that. Um, it, it,


[00:22:41] Ben: So, uh, so, so the, the, the question that Daphna was asking is, is as a physician scientist, um, how you engaging with. Um, with the private sector to sort of fast forward the tools available to patients at the bedside. Can, can you tell us a little bit about, um, the need that we have [00:23:00] in our current society to, to do more of this in order to speed things through for, for our patients


[00:23:06] Paul: yeah, that, that, that's a, that's a really interesting question. So when I, when I was at the National Institutes of Health, I just focused on a few diseases, studying them, making mouse models, zebrafish models, and a small group of patients with these rare diseases. And I've been at GDX for two and a half years.


[00:23:22] Paul: And it's really interesting in that I have more of a global perspective as chief medical officer of what's going on in the country. And instead of just focusing on a few diseases, we're focusing on all diseases, all rare diseases, and also Just the interactions, um, throughout North America with different hospital systems, different clinicians, patient advocacy groups.


[00:23:46] Paul: It's really been enlightening. I've learned a ton in the last two and a half years. I'm really glad I did it. And also I, I, I, the, the biggest thing I've learned is that the diagnostic odyssey, um, [00:24:00] and the shortage of, of, of clinical geneticists is real out there. I never realized. the magnitude of these concepts when I was at the NIH.


[00:24:09] Paul: So it's really been fun and fulfilling to, to, to promote implementation of genetic testing. Um, and, and travel around the United States and, and, and meet different people and, and learn more about the, the genomics community and rare disease community.


[00:24:31] Ben: Paul, we're coming to the end of our interview. I guess my, my last question is, uh, related to, uh, things you guys are currently working on that, that you're all, um, pretty excited about. I think we were talking off air about, um, about, uh, a study that you're currently, uh, doing in, in New York. Can you, can you tell us a


[00:24:49] Paul: Yes. Um, so this is a little different. We're shifting gears from the NICU to the, the newborn nursery. So we're doing a study called the Guardian study. And that's in [00:25:00] partnership with Columbia University. The principal investigator there is Wendy Chung. Uh, Illumina, who, uh, produces a lot of the sequencing machines in the U.


[00:25:09] Paul: S. and the, and the New York State Department of Health. So we're all partnering to do whole genome sequencing. On infants, presumably healthy infants, and we're only looking right now at about 240 genes. Um, so we're pulling that off the whole genome sequencing, and the idea is to find conditions that we can intervene before the infants become symptomatic.


[00:25:34] Paul: And it's really exciting work. Um, it's groundbreaking. There's a lot of questions really to be answered. So, um, we're, we're working on our first manuscript. We presented our first thousand cases at the American College of Medical Genetics this spring. So it's, it's really, it's really interesting work and fulfilling.


[00:25:52] Paul: And again, getting back to, um, the diagnostic odyssey, it really has the potential to, to evaporate it.[00:26:00]


[00:26:02] Ben: How is that different from from


[00:26:04] Paul: Yeah, so the current newborn screen is dictated by Health and Human Services, known as the Recommended Uniform Screening Panel. So right now, it's about 36 conditions. Most of them come off the TAN MS spectrometry technology that was introduced when I was in medical school in the early 1990s. And that's really only looking for inborn errors in metabolism.


[00:26:28] Paul: So there's a limitation, um, to, to that type of testing. Now we can really expand, um, into genetic testing. Now I did skip two conditions. There are two DNA conditions that are screened for, um, that are on the rough. And, and one is spinal muscular atrophy. And this is a relatively common in our field, um, neurodegenerative disorder where the life expectancy is less than two years of age.


[00:26:54] Paul: And I'm saying this for the audience, obviously you, you too know this. And then also SCID, severe [00:27:00] combined immune deficiency. Those are two DNA tests that we are screening for, but now we're looking at potentially we could expand, this could be an unlimited, um, um, expansion of, of newborn screening. So,


[00:27:15] Ben: That's very exciting. And you mentioned the rusps if you um, if people have any, any. Questions about what the recipe is and so on. And the newborn screening, uh, I recommend listening to episode 124 of the podcast, where we hosted, uh, Dr. Beth Tarini, who, uh, talked about the newborn screening saves lives act and where she goes into a lot of details about the inception and the current state of the newborn screening.


[00:27:37] Ben: Um, Paul Kriska, thank you so much for making time to, um, to talk to us today about Gene Dx. People can find out more about GeneDx at, uh, www.genedx.com. We will link all these resources on the episode page. We will also link to some of the articles that you've mentioned and ways to get [00:28:00] in touch with the team at GeneDx.


[00:28:01] Ben: Thank you very much for making the time and for all the work that you do making, uh, genetic testing widely


[00:28:07] Paul: Ben and Daphna, thank you so much for having me.


[00:28:13] Ben: Thank you.



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