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Healthier World with Quest Diagnostics
40 - Unlocking answers faster with whole exome sequencing (17 min)
00:17:20
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- [00:04]
A
Welcome to Healthier World with Quest Diagnostics. Our goal is to prompt action from insight as we keep you up to date on current clinical and diagnostic topics to transform lives and illuminate a path to better health.
- [00:19]
B
We've gone from testing one gene at a time to analyzing nearly all of them at once. So what changes for patients and providers? Rebecca I'm Rebecca Johnson Wheeler, a certified genetic counselor, and today I'm joined by Steve Kyles, executive director and general manager of specialty genetics here at Quest Diagnostics, to discuss how advances in whole exome sequencing are expanding clinical applications, helping patients get answers faster while also improving targeted treatment and care. Thanks for joining me today, Steve.
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C
Thanks for having me.
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B
Before we dive in, I would love for you to talk a little bit about yourself and your background.
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C
Sure. I started out as a practicing genetic counselor, so I'm a genetic counselor by training. Worked in clinic for over 15 years, seeing patients of all different types, from pediatric, prenatal to adult. I've been in the lab side of the business now for about 25 years, working in a startup lab prior to my time here at Quest. I've been at Quest now over 11 years and my role here is to oversee the genetic business that Quest provides. And my team supports all of the hereditary testing that Quest does across all different specialties, including women's health, prenatal oncology, and what we call specialty genetics or rare disease. When we look at the history of Quest, we can see that genetic testing has been around for well over 30 years and we we've changed dramatically. As you pointed out in the opening, how we can test multiple genes and in many cases all the genes in one specific test. In my current general manager role of specialty genetics, we are focusing on rare disease, neuromuscular diseases, and we have a whole exome test which is the ability to test all the genes.
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B
I don't think people realize how long genetic testing has actually been around, especially here at Quest Diagnostics. But more specifically, thinking about whole exome sequencing, can you talk a little bit about how it's changing the genetic landscape?
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C
Sure. First, it's not a new test. It's actually been around a long time, but it is being utilized differently across the space. And this was available over a dozen years ago, but it was very different in that it was not generally used in the mainstream. It was more research. Insurances didn't pay for it. Insurance coverage has changed. It was a long journey to get to that. So there were often a few genes tested at one time and it would go through a series of reflex testings or an approach where the smaller number of genes or the most likely genes were started first. And with each test you would have costs associated with it. So what we've seen is this journey to get to a diagnosis, which in some cases required many tests and still didn't give you an answer, but you would have spent a lot trying. One way to think about it is what makes sense from a diagnostic standpoint. So in some cases these smaller tests do make sense, where there is a defined phenotype, where the genes that are known to cause some of these conditions are known and well documented and the payers will pay for those specific tests. So we see that a lot of in some areas of specialty around hereditary cancer, pharmacogenetics, cardiovascular, but when you start getting into rare disease and some of the other specialties, the disease specific panels are not necessarily going to find everything. And as I said, with the technology change, the costs have really come down. So you could make the argument that it's more cost effective in many cases to start with an exome, because you get an answer in a large portion of the testing and you get to that answer much faster. So these diagnostic odysseys that can sometimes take five or 10 years to get through to a diagnosis can now happen in some cases months. And so we're starting to see more guidelines support whole exome testing. This is becoming more of a first line test for more and more clinicians, especially in the rare disease patient population. So we see this in specialty pediatrics, developmental pediatrics, pediatric neurologists. And as the exome becomes more standard, we're seeing more insurance coverage, we're seeing patients get more access to it and it will rapidly change the timeline, especially when there's therapy or treatment decisions, which we're starting to see more and more that there's targets for specific drugs or treatments where they need to confirm the diagnosis. And the faster you get to that, the faster you can start either changing treatment or initiating treatment, which is huge for patients and their families. We're starting to see the shift. The end of last year, the American Academy of Pediatrics started recommending testing for exome when it makes sense clinically to alleviate the long wait for referral to specialists and then start testing and then referral for follow up and in some cases can add a year or two to this journey. Whereas primary care pediatricians can get right to the diagnostic information and then make the appropriate follow up and referrals in a much faster timeline.
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B
So the testing is becoming more accessible and gaining Some traction when thinking about that. How often are we finding actionable results on whole exome sequencing?
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C
That's a great question. Oftentimes, when you look at how often we find a diagnosis, it is actually much greater than what we've seen in the past when we've identified, you know, specific genes or small numbers of genes. So it does depend on the symptoms. What's really important is to identify what are the clinical symptoms and using those symptoms to help get us to a diagnosis. On the low end, we're probably seeing 15 to 25%, depending on the symptoms, where we can come up with a diagnosis. But we've also seen 25 to 50%. When there are certain diagnostic clinical findings that we can use, like a newborn who's having seizures and has some other symptoms around physical anomalies right after birth, we'll see a much higher positivity rate. Those might be closer to 50%. Whereas if you have a newborn that might only have a few symptoms, there's no seizures, we might see things closer to 25%.
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B
That still leaves quite a few patients without an answer. What about those families and individuals who are still seeking answers but have a negative whole exome result?
- [07:10]
C
That's a valid point. It's something we do see in genetics in general when we've done diagnostic testing historically. Oftentimes the positivity rate might be less than 10%. So it's a huge increase. But you're right, there's still a lot that don't get an answer. So one of the things that's important is that we follow those kids to see what other things are happening as they develop. So if you have a newborn and you do an exome, you're only going to know what is happening in the newborn period. From a developmental standpoint, you can't be developmentally delayed as a newborn, but as the child ages 3 months, 6 months, 9 months, now you're having more milestones, you're getting more clinical information. They may develop other symptoms. And so it would be important to potentially come back to that exome. And this one makes exome so helpful. Once the data's there, it's there. You can reanalyze it with new clinical information that might actually lead to an answer. You also want to make sure when you're doing the exome that you're including all the pieces that could have a known variant, that would be types of variants like large deletions and duplications. So we want to make sure we're looking at that. The mitochondrial DNA is important. It does make up a percentage. It's important to know what kind of exome and what was included in that. So if somebody had an exome where the mitochondrial or copy number variants were not included, it would be important to get those looked at as well. Ideally, you want to have all of those wrapped up into one test, which is what we do here at Quest. So you get a comprehensive exome, including all relevant variant types. The other thing is sometimes you can get a variant that looks suspicious for a particular condition, but we don't have enough information about that variant to know for certain whether it's pathogenic or not. And these are reported out as variants of unknown significance or vus. And again, that would be important to check back as the lab and the clinical information that is out there increases over time. So we might be able to reclassify some of these variants from an unknown to a known whether it's pathogenic or not, based on growing data and clinical information and other patients and what we see both internally as well as in the literature.
- [09:37]
B
You mentioned a lot of ways that laboratories are continuing to look at data, which can be a lot of data, considering a lot of whole exome sequencing tests include both the patient and their parents for what we call trio testing. So beyond reanalysis and variant interpretation, how else are the labs helping to improve outcomes and supporting the providers, their patients and their families through the testing journeys?
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C
This actually is a big area of support for us. We are there for the entire process, not just to provide results and answer questions, but really we can help the clinicians throughout the entire process, starting with ordering, interpreting and providing follow up to the patients. We have a whole team of genetic counselors that are trained in this area that can answer questions every day. And we get questions from clinicians, we get questions from patients, and we're happy to provide support. There's a wide range of expertise within genetics. Not every clinician has had genetic training. Some have more experience than others. And so when we're dealing with primary care, other areas of specialty where they don't see genetics as frequently or maybe don't have as much experience with ordering these kinds of tests, we can really help them through the process to understand what are the options, what may be the most appropriate test we can help assess if there's going to be additional family members, Ideally for exome, you don't just look at the proban, which is the patient, you're also looking at a couple of family members. So this way you can compare the DNA that helps with the Analysis. So when you have a child with both mom and dad DNA and you can compare all the three, you're actually going to get a better result a greater percentage of the time. And so understanding when maybe only one parent is available, that's going to be more helpful than if it's just the patient. But if we have all three, we have both parents and the child, then that's going to give us much more information. We're also there to help with getting the clinician to understand the value of all the clinical history and the clinical results that they have from any test that they might have performed. Whether It's CT scans, MRIs, things like that. All that information will help us with interpretation and getting to a diagnosis. One of the other benefits here at Quest, both from a testing and resulting standpoint, is in these cases where we do find a diagnosis that might put somebody at risk for kidney failure or cardiovascular disease or some of the other organization failures or problems that you would want to track. Here at Quest, we have all the basic monitoring tests focused around this. So patient wouldn't have to go very far to get these kinds of tests incorporated into their care. And we can provide the whole spectrum of testing and screening for those patients. That is something that can be really helpful for many patients when there is a diagnosis that is made. This is one of the areas we specialize in here at Quest, which is providing clinical expertise we are here to support. Not all labs offer this, so that would be something to look at when choosing a laboratory. In some cases the clinician may be on their own or have to reach out to other resources for interpretation and recommendations. But like I said, that's something we specialize in. We are really proud of that and have been able to help a lot of families and clinicians along the way.
- [13:11]
B
That's an important thing to highlight. Having these genetic resources readily available can have a big impact. We recently had a provider contact us to say that she normally orders gene panels for her patients and this time she ordered an exome and actually found an explanation for her patients features in a gene invariant that were not included on the panel she normally orders. So in this case we were able to connect her with a clinical specialist who had published the original cohort studies for the condition and and they were able to discuss a management plan and care for this patient. Just wrapping up our conversation on whole exome sequencing. Are there any final thoughts that you'd like to share?
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C
There are a couple of things. If you look at genetic testing for rare disease and even some Common diseases. Many people would say, why? It doesn't really matter what the underlying cause is. If the patient has developmental delay or the patient has seizures or. Or the patient has a suspicious diagnosis, why is it so important to confirm it with genetics? 20 to 30 years ago, there was really no treatment for almost any of these conditions. So it was really just to confirm what the condition was. Maybe that would help the family, but from a treatment and next steps, it wouldn't make as much of a difference. But in the last 20 to 30 years, we've seen a huge change in the pharma world. Targeting now rare disease, targeting genetic conditions with treatments that can change outcome dramatically. 25 years ago, when we were doing cystic fibrosis testing, many of the clinics said, it doesn't matter. I know the patient has cf, what good is finding their variants? Whereas the majority of CF clinics knew that there's going to be a treatment and when that treatment comes, that's not when I want to start genotyping all my patients. I want to know who's got what variants. So as soon as these treatments become available, these patients would be eligible. And that's exactly what happened. The drug company started coming out with treatments targeting cystic fibrosis. And many of the targets were very specific variants. So this drug only worked with a Delta F508 variant, or this drug would only work with a stop codon variant. And now we see more and more treatments targeting variants or targeting the diagnosis, and we start seeing more of a benefit for the pharma companies to invest. They can narrow who will benefit and who won't. You tend not to see adverse reactions, you tend to see more success, and it's easier for FDA approval. And we're seeing part of the development is that there's a requirement for some of these drugs, a black box label around. In order to qualify for this drug, you need to have a variant in this gene. And so when people say to me, what am I going to do with these exome results? My answer is, I gotta see the results first. You might have a whole change of regimen of treatment. In addition, when we make a diagnosis, we know that the diagnosis might also put somebody at risk for other problems, whether it be kidney problems, heart problems. So screening and following by those specialists could then be implemented in advance of developing symptoms. So I think that is the big difference that we see going forward. There's a lot of benefit and it's only gonna increase as we make more discoveries. There's more diseases that have treatments and we are finding that we can change lives on a daily basis. So it's pretty exciting to be involved in this and to see the success and the benefits that are being translated to patients across the board.
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B
Yeah, I agree. It really is an exciting time. Well, thanks so much for joining me today, Steve. It was wonderful to chat with you about how whole EXOME sequencing has evolved and how it's having such a large impact on so many lives.
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C
It's been great to be here and sharing this, and thank you so much for having me.
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A
That's a wrap on this episode of Healthier World with Quest Diagnostics. Please follow us on your favorite podcast app and be sure to check out Quest Diagnostics Clinical Education center for more resources, including educational webinars and research publications. Thank you for joining us today as we work to create a healthier world, one life at a time.