Search for tag: "genetic"

Interviewer: With the power of computers behind them, scientists are solving the mysteries of undiagnosed diseases, up next on The Scope.

Announcer: Examining the latest research and telling you about the latest breakthroughs, the Science and Research Show is on The Scope.

Interviewer: I'm talking with Dr. Aaron Quinlan, associate director of the USTAR Center for Genetic Discovery at the University of Utah. Dr. Quinlan, you recently had some really exciting results using technologies that your group developed. They may have helped solve a health mystery. This is about infants with a particular condition. What was going on?

Dr. Quinlan: We were studying infants with seizure disorders, and the genetic basis of those seizure disorders was unsolved.

Interviewer: So, the idea is that . . . I mean, obviously they had seizures, presumably pretty severe ones, but doctors didn't know what was causing it. So, there were about a dozen or cases, and you were able to possibly find the cause for most of them?

Dr. Quinlan: Yeah, for the majority, I guess 90% of the cases we have a pretty clear candidate that we feel strongly about, and in 9 or 10 of those cases, it's a mutation in a gene that is known to cause this phenotype but was not picked up via standard clinical diagnostic tests, and in a handful of other cases, we think we have discovered new genes that underlie this phenotype.

From a clinical perspective, there's a transition, certainly removing very rapidly from gene panel tests, where we only look at a very, very small subset of the genome to interrogate genes that we know cause a given disease phenotype to, I think, in the coming years, it will be a standard course of care to use exome or genome sequencing to do this diagnosis because it's so effective, and I think the clinicians that we were working with were very excited about the accuracy and the rapidity with which we could make these predictions.

Interviewer: The role of you and your group in this is that you've developed a computational tool called Gemini, and that's what led to these results. What is Gemini?

Dr. Quinlan: So, we used genome sequencing of both the infant and their parents to try and identify genetic mutations, essentially, that cause the disease phenotype in question, and this process requires a broad spectrum of computational methods, everything from rapidly and accurately processing the sequencing data to identifying genetic variants that exist in these families, and then finally to essentially get back to a needle in the haystack problem of what is the single genetic mutation that causes the phenotype and isolate that from the potentially millions of genetic variants that are benign but exist in these infant genomes.

So, the idea is that Gemini takes all the genetic variation that's observed in the genomes or exomes of all the individuals that you're studying, and it integrates all that genetic variation information with the extreme wealth of genome annotations and reference databases that we have. For instance, some people might be familiar with OMIM. It's a list of all the known mutations or genetic variants and genes that are associated with diseases.

Interviewer: Right, so keeping up with the pace of research, the pace of knowledge.

Dr. Quinlan: Right. It's an incredibly demanding problem because there's probably 50 to 60 reference databases that we try to use, and they're all evolving. They all have mistakes. Those mistakes are fixed, and you've gotta propagate those fixes to the mistakes as quickly as possible so that . . . what we're trying to do here is empower discovery for human genetics, and so, having the latest and greatest information, obviously, empowers that process.

Interviewer: So, is there somebody who's monitoring each of those databases and saying, "Oh, gotta update, gotta update, gotta update"?

Dr. Quinlan: Yeah, we have people in the lab who monitor that, but, believe me, the research community that uses this software, they monitor it as well.

Interviewer: And so, the real tricky part is that a lot of us have scads, you can give me the numbers, you know, scads of variations in our genome, and so that the problem is finding the one or ones that increase risk for a certain disease.

Dr. Quinlan: That's right. I mean, any two individuals differ by about 3,000,000 to 4,000,000 genetic variants. So, when you look at a family, do a whole genome sequencing of an entire family, you're going to find on the order of 3,000,000 to 10,000,000 genetic variants that you have to sift through. Now, many of those, admittedly, are very simple to ignore, especially for rare disease phenotypes. We typically focus on genetic variants that affect protein coating genes. But even when you do that, you're talking about on the order of 18,000 to 20,000 genetic variants that need to be considered, and so, we need to be able to do that in a quick and reproducible way, and we want to minimize false predictions, but I think even more concerning are real genetic variants that may be associated with the phenotype that you miss. So, we want to essentially find everything but don't over-predict.

Interviewer: I imagine you spend a good part of your day in front of a computer screen. I'm wondering do you think about how this sequence of letters you have in front of you is actually a real person.

Dr. Quinlan: Yeah. Admittedly, I am fairly disconnected. I'm a genetic researcher that spends 12 to 15 hours a day in front of a computer, and I'm not a clinician, so, I don't interact with patients on a day-to-day basis. However, I mean, that is our motivation here, is, you know, that was the main reason I moved my lab from the University of Virginia to the University of Utah was to have that connection.

We have a very nice interaction between researchers and clinicians here at the U, and I think it really helps to bring home the reality of these cases. We meet with the doctors who actually work with these patients, and when you understand their plight both in terms of the diagnostic odyssey and also the impact on these families, both in the short and long term, it makes it very real.

I would like to be able to provide a resource to try and solve rare disorders in Utah, nationally, and not only retrospectively for families that are sort of pursuing this diagnostic odyssey, but also to have a system where this can be done in real time in collaboration with clinicians in our hospital and other hospitals so that when there's an infant that comes through the NICU or there's some pediatric genetic disorder that is perplexing, we have a system in place where we can sequence the genomes and actually bring our tools to bear on solving that problem quickly and as accurately as possible.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.

Interviewer: What are the symptoms of HHT and what should you do about it? We'll talk about that next on The Scope.

Announcer: Health tips, medical news, research and more for a happier, healthier life. From University of Utah Health Sciences, this is The Scope.

Interviewer: Nine out of 10 people with the genetic disorder HHT are still undiagnosed. What makes it so difficult is it can have multiple and seemingly unrelated symptoms. If not treated properly, it can have dire consequences. Jamie McDonald is a licensed genetic counselor and Co-Director of the HHT Center of Excellence at University Utah Health Care. I'm not going to attempt to say it. I'd like you to say it and maybe I'll try afterward. What does HHT stand for?

Jamie: It stands for hereditary hemorrhagic telangiectasia. Hereditary, of course, means it runs in families. Hemorrhagic means that it is associated with bleeding. And the word "telangiectasia" that indeed, one has to hear about 50 times to be able to say, refers to a very specific type of blood vessel abnormality. It is, in particular, a blood vessel that is abnormal because an artery is directly connected to a vein rather than connected via a capillary network, which is the normal thing.

Interviewer: And different places, different people have it in different places and different quantities of them? Some people might have a few, some people might have a lot?

Jamie: Exactly. That is the case that there is huge variability and surprising to even many physicians that don't see a lot of this disorder, it's variable even within the same family. So it would be reasonable to expect that if a parent had certain manifestations of this disorder or a certain severity of different manifestations, then maybe it would be likely that their child would as well. It's absolutely not the case. It's very variable from person to person, even within the same family.

Interviewer: And it is a genetic issue, as we've established before so it's hereditary. Why are we just now hearing about it?

Jamie: The fact that 1 in 5000 people are affected rather than the frequency with which people have diabetes or congestive heart failure has decreased the chance that people are going to become aware of it.

Interviewer: So it's something that affects even 1 in 5000 doesn't sound like a lot, it can turn out to be quite a few.

Jamie: Absolutely. And those of us that see many HHT families and sort of collect them, if you will, because we focus on this disorder, feel that 1 in 5000 probably is a significant underrepresentation. When I see families and take a three to four generation family history, as I do, all of a sudden, after having asked the right questions about those family members, I have in front of me on my family tree a pedigree of five people in my patient's family that clearly have HHT but haven't been diagnosed because the pieces of the puzzle haven't been put together.

Interviewer: Let's talk about some of those pieces. What are some of the symptoms that people might have? I've heard nosebleeds commonly referred to. Is that one of the main ones?

Jamie: Absolutely. It is the main one. About 95% of people with HHT will have recurring nosebleeds by the time they're adults, say, 40 years of age. But recurring may mean one every two weeks or it may mean two an hour. So it's extremely variable and you can imagine that if somebody has one nosebleed every two weeks that stops in a minute's time, they may not have even reported that to their physician. So it's the cardinal, most common feature, but not the feature we're most worried about.
The features we're most worried about are the larger, abnormal blood vessels we call AVMs or arterial venous malformations, that can occur in the lung and the brain and liver and lay hidden unless you go looking for the because you've been tipped off that they might be there based on the person's history and family history of nosebleeds. And then, the second thing that can actually be seen on the outside of the body, before we start doing fancy imaging tests to look inside the body, are little tiny telangiectasias or what show up as red spots on the hands, mouth, face of the body.

Interviewer: And are those red spots there all the time?

Jamie: They're there all the time. They don't come and go like a rash would, for example. They're there all the time. Although, people tend to develop more of then with age. At birth, a baby that's born with HHT, for example, because, after all, it's hereditary, a baby gets HHT by inheriting it from a mom or dad. So it's there at birth in some fashion or another. But, usually, the telangiectasias on the skin don't show up until adulthood.

So one of our key concerns as we work our way through families where many people aren't diagnosed yet is people will develop an AVM in their brain in this disorder, usually, years before they actually develop the nosebleeds and red spots on the outside. So the underlying features of HHT that we're most concerned about don't jump out at doctors when they see these patients in their clinics.

Interviewer: The symptoms might not show up so what are some of the damages of this?

Jamie: The significant damage is the baby that has a brain bleed or brain hemorrhage from a ruptured AVM at three years of age before they've had a chance to develop the nosebleeds that begin at average age 11, 12 or red spots on the outside on the skin, which develop average age 20s or 30s. The brain bleed can occur in a young child from an AVM in the brain or a 30-year-old can have a stroke or a brain abscess due to a lung AVM. The blood isn't being filtered out of clots each time it circulates the body and passes through the lungs.

If blood goes through an AVM in the lung and the clot isn't filtered out and that blood then goes to the brain, it's a stroke. So strokes, both of hemorrhagic nature and of a clot blocking off a blood vessel nature, are both risk factors for people with HHT that haven't ben appropriately diagnosed and screened.

Interviewer: So what do you do? How do you find out if you have it if you're not showing the symptoms of the nosebleeds? I guess, first of all, if you have fairly consistent nosebleeds, you probably should go do a little bit more research on that and see if you have HHT.

Jamie: Absolutely.

Interviewer: I could have it and not know it, right?

Jamie: Absolutely. The key there is once HHT is identified in a family in someone old enough to have the nosebleeds and the red spots on the skin and/or brain hemorrhage that leads to the diagnosis, to not let the evaluation stop there. When we have a patient come to our clinic and say it's a 50-year-old mother and grandmother, and we make the diagnosis of HHT, there's an evaluation we're going to do for her to make sure she doesn't have one of these hidden time bomb AVMs inside an internal organ. But, from our perspective, the whole family has become our patient. We're going to talk to her about her kids, her grandkids and what they should have in the way of testing.

At this point, thankfully, genetic testing for HHT is available. I can draw a blood sample on that 50-year-old mother/grandmother we just diagnosed with HHT and prove in her down at the genetic level what's causing her HHT, exactly which gene and which mutation in which gene is causing her HHT. Because it's different in each family with this disorder. But once I've pinpointed that in one member of the family, I know that anybody in that family that inherited the HHT will have that exact same mutation. So I can now test her kids and grandkids.

Interviewer: So the key is to think, "Huh, did Uncle Al have regular nosebleeds all the time? He did and he always complained about them. Hmm."

Jamie: Exactly. Exactly.

Interviewer: All right.

Jamie: But again, these are pieces of the puzzle that had to be put together in order to come up with a diagnosis. Often times, it requires looking at the whole family, not jus the individual in front of you.

Interviewer: Most of your patients, do they figure this out on their own or they have a doctor help them?

Jamie: It's a combination. Oftentimes, an astute physician suspects it originally, oftentimes in a member of the gamily that has a particular number of manifestations and then after having had that diagnosis floated to the patient by a primary care doc, the patient gets on the Internet, finds out that there actually are specialty centers and specialty clinics for this rare disorder and makes their way to either us or one of the other specialty centers.

Interviewer: That sounds like if you think you might have it, the next step for most people is to find the specialty center, like here at University of Utah Health Care. If somebody's looking for more information about HHT, do you have a resource that you recommend to somebody?

Jamie: Absolutely. There's a national group called CureHHT, formerly known as the HHT Foundation, that is a resource for patients and physicians alike, including a list of HHT centers of excellence nationally.

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Jamie:

Interviewer:

Interviewer: Managing medications through genetic testing, up next on The Scope.

Announcer: Examining the latest research, and telling you about the latest breakthroughs, The Science and Research Show is on The Scope.

Interviewer: I'm talking with Dr. Diana Brixner, Professor of Pharmacotherapy and Director of the Outcomes Research Center, and Director of Outcomes for the Programs and Personalized Health at the University of Utah. I wanted to talk today about a study that you led recently looking at the elderly who, amazingly, on average take at least 14 prescribed drugs each year. What are some of the concerns about that?

Dr. Brixner: All of us have different variants of drug metabolizing enzymes, and this will have an impact on how many drugs are, in fact, metabolized. So as you can imagine, in individuals where you are not aware of what the drug metabolizing enzymes can do, you may likely under-dose or overdose an individual. It could lead to adverse drug events. It could also lead to increased drug interactions where two drugs may be overactive where you did not anticipate that.
With the elderly, they do, in fact, take many more drugs, and because they're on more drugs, then the risk of drug-drug interactions or drug-gene interactions between the drugs that are on is much higher. And therefore, using a test to determine their variants in drug metabolizing enzymes can be very valuable.

Interviewer: So what kind of test did you perform on them? I mean, it was more than just a test.

Dr. Brixner: Yes, and that's what makes this product really very interesting. It's a combination of the test, which is done via a buccal swab, and then the gene analysis is done in a certified laboratory. But the results of that test then are run through a clinical decision support tool, and the combination of the test and the support tool is called YouScript, produced by Genelex Corporation in Seattle.
And what the clinical decision support tool does is it takes in account not only the drugs susceptible to these enzymes, but in fact, all the drugs the patient is on. And therefore you get a very complete picture of drug-drug interactions, drug-gene interactions and drug-drug-gene interactions. Let me give you an example, if a patient is on a drug that has an interaction, and then has a drug metabolizing enzyme that affects another drug, it's very likely that that could lead to a drug-drug interaction you would not have ordinarily expected without knowing the genetic information from the patient.

Interviewer: And so, by taking together the results of the test with the results of this clinical support tool, you can modify somebody's drug regimen based on what you think will be least likely to have adverse reactions for that patient?

Dr. Brixner: Yes, that is ultimately the idea, and that, again, comes back to the idea of the clinical pharmacist, and the role that the clinical pharmacist can play in actually interpreting the results of the clinical decisions support tool with the provider and the patient, to then make the appropriate modifications in their therapy regimens so that the patient gets the best benefit with the least exposure to adverse events.

Interviewer: So you got some really striking results from this study.

Dr. Brixner: What we found was that, in the group that was tested, there were significantly lower emergency department visits and hospitalizations than in the group that was matched and not tested. What's interesting is that we also saw actually an increase of outpatient visits in the patients that were tested, which was counterintuitive at the outset. However, when you think about it, in fact, these results make a lot of sense. If patients are tested upfront, it's likely that patients would come in to the provider and have additional outpatient visits then, not only to review the results, but make any appropriate changes to their therapeutic regimens.

Interviewer: And the decrease in hospitalizations and emergency department visits that you saw actually took place over a pretty short follow-up period, right?

Dr. Brixner: Yeah, that's a very interesting point to bring up. Our study looked at a four-month follow-up. And, in fact, we are now currently looking at extended data out to nine months, and we would anticipate that the impact of the savings would be even greater at nine months out to a year, granted there is a point where there are no additional savings. But the other interesting point is that you only need to be tested once, and this information then can be put into the elderly patients file, and then as they bring on new drugs, or change drugs going forward through the rest of their life, this information can be used to guide appropriate treatment.

Interviewer: And you talked about savings. You mean costs savings?

Dr. Brixner: The savings was, in fact, there is the cost of the test and the clinical decisions support, but there is also then cost savings by the emergency department visits and hospitalizations avoided. So what we did using some national costing data is demonstrate that, in fact, the majority of the cost of the test is offset by the savings and fewer emergency department visits and hospitalizations.

Interviewer: So this is a test that, at this point, probably is not covered by most insurance policies, or at least by Medicare, who most of these patients would be with.

Dr. Brixner: And that was exactly why we set out to do this study in the first place. It is a very dynamic environment right now with when looking at how data should be considered for making reimbursement decisions around diagnostic tests. And that includes the test that we're talking about today, preemptive pharmacogenetic testing, as well as the gene testing for targeting drug therapy. It's a different process to look at reimbursement for diagnostic test than it is for drugs. And Medicare and other insurance companies are struggling with how this evidence should be evaluated.
Our hope was to generate enough evidence that would look potentially favorably at the inclusion of this type of a test and clinic decision support tool in managing elderly patients on several drugs or polypharmacy, that we would then go ahead and validate our findings in a larger prospective randomized trial design. It's exactly that type of study that we're working on now, based on our preliminary results to demonstrate the validity of our results in a unified population within one health care system.

Interviewer: What's your hope for where this type of work is going?

Dr. Brixner: Well, that's great question. What I would love to see is that when we do the validation study that we see trends along the same line as what we saw with our preliminary results. I then think it would really be worth considering that when the elderly come in for their annual well visit, as they enter into the Medicare health system, that they should, in fact, have this test done once, so that it's in their file to guide their future treatment regimens. To me this would be a great step forward in improving care for the elderly, and greater involving clinical pharmacists in the role of medication management.

Announcer: Interesting, informative, and all the name of better health. This is The Scope Health Sciences Radio.

Interviewer: Should every woman over 30 receive genetic testing for breast cancer? Up next on The Scope. Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.
I'm talking with Wendy Kohlmann, a genetic counselor at the Huntsman Cancer Institute at the University of Utah. Ms. Kohlmann, explain the viewpoint that was published this month in the Journal of the American Medical Association.

Wendy: Dr. Mary-Claire King gave a very thought provoking presentation and article regarding the idea of population based screening of the BRCA1 and the BRCA2 genes. Typically we have relied on the tool of family history to help us identify families that maybe have mutations in these high risk genes.
We looked for families that have features such as multiple women with breast or ovarian cancer, women who develop breast cancer at younger than average ages, women who develop both breast and ovarian cancer or perhaps bilateral breast cancer. Those were all red flags that maybe there was a mutation in one of these genes being passed through the family.
Dr. King suggested kind of a new approach to this. Rather than relying on family history as the tool for identifying families that may be at risk she suggested that it may be beneficial to think about just testing all women for this mutation.

Interviewer: Why focus on the BRCA genes?

Wendy: Mutations in those genes are quite rare; however, when a mutation does occur the risks in these families is greatly increased. The risk for breast cancer can go up to 50 to 80% and the risk for ovarian cancer can be elevated as high as 60%.
Also there are very well established screening and prevention recommendations for women with mutations in these genes. We can screen for breast cancer at an earlier age or more carefully using things like mammograms and breast MRI's, some women also opt for prophylactic surgery to remove the breast or ovaries before cancer develops, so Dr. King's argument was that even though these mutations are uncommon, you know, if they are present in a family the risks are very high and there are very specific things that the women in those families could do to reduce their risk if they were alerted in advance.

Interviewer: So why does she think that knowing the family history may not be good enough?

Wendy: Some families are just very small and there are few relatives and it's hard to see a strong pattern. Also, for mutations in genes such as BRCA1 and 2 that tend to cause an increased risk for cancers, most specifically in women, if you have a family that just happens to have lots of male relatives as opposed to females, this mutation could be passed through generations of men who don't develop the cancer and we won't see that until it shows up in finally a female granddaughter for instance.

Interviewer: But I thought mutations in BRCA could cause breast cancer even in men.

Wendy: They can, the risk for a man with the BRCA mutation to develop breast cancer is only about 6%.

Interviewer: And do we have a sense of how many women do not get tested for BRCA that actually carry the gene?

Wendy: We are probably missing a fair number. We recently completed a study at Huntsman that was looking statewide at women who meet the current guidelines for genetic testing which are based on family history and we contacted women throughout the state and found that of women who meet current genetic testing guidelines, only about 20 to 30% of them had previously been tested so certainly, there are barriers to this getting done.
Some of it is information, some of these women reported that their doctor had never brought it up to them, they weren't aware that this testing was available. Other barriers are cost and insurance coverage which can still be a problem.

Interviewer: So her recommendation is in addition to you know, your typical mammogram, she's recommending that women over 30 undergo testing for the BRCA gene. What do you think about that recommendation?

Wendy: At this point in time there are lots of steps or pieces that would need to be put in place before we could really begin something like that very effectively. Dr. King, kind of based her recommendation on a recent study that she did in Israel and individuals of Jewish ancestry, there are three common mutations in the BRCA1 and 2 genes that account for the majority of hereditary breast/ovarian cancer in that population.
So in that population the likelihood of having a mutation is much higher than in individuals who don't have Jewish ancestry and also the testing is much simpler because we only have to look for three mutations as opposed to looking for the thousands of mutations that have been identified in individuals of non-Jewish ancestry so it's a little hard to take that study and say, okay now we can do this for everybody in any country.

Interviewer: With the thousands of mutations in BRCA that have been found are all of them high risk factors for developing breast cancer?

Wendy: So not all variations identified in a gene will necessarily be associated with disease risk and this is really one of the big challenges that we need to address before we could implement population based genetic testing of these genes. Sometimes changes will be identified in the gene and it's not clear whether or not that is, you know, that change in the genetic code would actually damage the protein being produced by that gene or if it's just part of kind of what makes everybody unique.

Interviewer: Right and I guess some of it is psychological. I mean, if you know that you have variations it may cause anxiety even though we don't know if there's really a basis to be worried about those results.

Wendy: You know, that can certainly be part of it. Studies have shown this that women who are found to have these variants of uncertain significance, in some cases have almost as much as anxiety as women who are found to have mutations because they've been told, well, we've found something but we don't know what it means and so there can be anxiety that goes along with uncertain findings.

Interviewer: You would say that at this point we're not quite ready for population based testing because we don't know how to interpret all the information that may come back. Are there any other factors we should take into consideration?

Wendy: Lots of logistical issues would probably need to be addressed before we could, in a really cost effective way, do the whole population. Right now there's a hodge podge of commercial laboratories throughout the country offering BRCA testing. Each one may be using slightly different technology, each one may be interpreting some of these genetic variants a little bit differently.
We also don't have consistent and uniform ways of tracking genetic testing in a lot of electronic medical records so if a women has one doctor at age 30 who orders this test but then switches to another healthcare provider, how is that information going to follow her through the healthcare system, but like I said, and I think that, you know, having discussions like the one Dr. King has initiated is really going to help us start breaking down these problems and figuring out how to solve them.

Interviewer: And so what would your recommendation be at this point?

Wendy: So for women who have a family history of breast cancer, we do encourage them to talk to their doctors or contact Huntsman Cancer Institute for more information. Like I said, even among women who have a family history of breast cancer that is not necessarily indicative of BRCA1 and 2.
For women who don't have a family history of breast cancer, at this point in time, these tests are typically thousands of dollars and the likelihood of there being a mutation is very low so we would encourage them continue to work with their doctors, follow general population screening recommendations. In the future as our genetic testing technology evolves wider spread testing may become an option or even the recommendation.

Interviewer: Interesting, information and all in the name of better health. This is The Scope Health Sciences Radio.