Hi, this is Eric Prostowski, and welcome to another segment of EP&IP. We have a return guest. He did so well the first time I made him come back, Dr. Michael Ackerman, who is a triple threat. He is a professor of PEDS, as well as medicine and pharmacology at the Mayo Clinic, and also holds a chair in genetics. So Michael, welcome back. Thanks, Eric. It's great to be back. I'm glad I passed the test. Yes. Well, and for those who are very astute, you'll notice behind him now is not one can of Clorox, but two. Right, Michael? You've graduated to a two-Clorox office. Yeah, I know it's not the topic, but wash your hands and wear your mask. There you go. So I would like Mike Ackerman today to talk about a subject that really is troubling for clinicians. He came to our place and gave grand rounds a couple of years ago, and it really was enlightening, talking about these variants of unknown significance. So Michael, I'm actually going to start with a recent case I had in the office. It was a woman in her late 40s who came in with a diagnosis of probable long QT syndrome. Now, she's totally asymptomatic, no family history of anything. I reviewed the ECGs, and yes, one of them, one ECG had a corrected QT of about 470 to 480. So kind of borderline, but a bunch of others, including the one that day, were considerably less than normal. So like a dummy, I ran genetic testing just to see if it would help me. And guess what? It came back as a variant of unknown significance in one of the channels and talked to me or talked to us. What do I do with that? Yeah, Eric. You know, the VUS issue five years ago, we published a paper called Genetic Purgatory and Exposing the Variant of Uncertain or Unknown Significance issue, the VUS issue. And I don't think you were a dummy. You've never been a dummy, but I think your point is a really good one of, should I have ordered the genetic test in the first place? But you did, and now you get a result back that is ambiguous. And it's just like getting an ECG back that gives a finding of uncertain significance or an FUS, and then we have to resolve that. And I think for our listener in clinical EP, they may not know that your variant that you got back could have been graded five ways. It could have been called benign or likely benign, and you and I actually don't even see those because the companies don't even report those back. Or it could be called a VUS or likely pathogenic or pathogenic. Whenever you get a VUS, the most important thing to do is stop, read, pause, rethink. In other words, who did you get this VUS on? Was this on an irrefutable, no doubt about it, channelopathic patient with long QT syndrome and a short score of 10? Or was this on a, I really don't even know if I should order the genetic test in the first place. This case is so weak, so flimsy. And the reason why we need to make that commitment is the phenotype is the single greatest, most powerful adjudicator of moving the VUS needle from out of purgatory to likely pathogenic or even stronger, or putting it and tanking it all the way to benign and say, why did I even learn this variant? So phenotype is the most important. Your patient was kind of a weak case, and now you say, what about this VUS? So then the second part is, what gene is the VUS in? So not all VUSs are created equal. So if the report came back VUS in ACAP9, for example, a really, really minor gene for which we're not even sure if that's a true disease gene, well then that VUS, no matter how strong the phenotype was, is still stuck in VUS land and it's not getting out very easily. On the other hand, if they came back with the gene behind the VUS as KCNQ1, and you say, oh, wait a second, that's the LQT1 disease gene. That's a true disease gene that accounts for a 35% of all long QT syndrome. I better now see if I can connect the VUS to my patient. Weak phenotype, still a VUS. A phenotype where you, before you ordered the test, said, you know, I bet it's going to be LQT1 because the T waves look like LQT1. The pattern on the stress test looks like LQT1. I'm betting LQT1, and then it comes back as a VUS. That's only a VUS because the company did not have the knowledge set to grade it any higher than that based upon all of their tools, because they are missing what you and I have as the most powerful final arbiter, which is strength of phenotype. Those are some of the things I would have done to try to decide whether I blow off the VUS, or whether I have some more work to do for the VUS, or whether I can, in a split second, promote that variant from a VUS by company to a disease-causative pathogenic variant by the phenotyper. That's very, very useful. Let me tell you about another case, then, and see if you can follow through on this one. I had a patient not too long ago who had apical hypertrophic cardiomyopathy. I mean, clear cut, there wasn't any question about it on the ECG, classic ECG, you know, typical, and the listeners should understand this, if you have an ECG of apical hypertrophy and the echo doesn't pick it up, it doesn't mean it's not there. MRI will often pick it up that the echo missed. It's not today's topic, but just so they know. So I thought, well, I better, this would be a good thing to do, to try and run down a gene here. And I came up with a variant of unknown significance. And the question I have for you there, I mean, I knew the person had a disease, and I'll be honest, I can't remember in which of the many genes with, you know, with the HCF. What about family tracing, then? So can you trace a VUS? Is that something you can do? Yeah, that's a great question, because one of the things that can move a VUS is what's called co-segregation data. So if you have a variant, forget what the company graded it as, and you have a collection of family members that all are given exhibit A, they're showing the phenotype, apical HCM in the case of your patient. And now that variant of interest is tracking through all the people who show exhibit A. Well, that co-segregation concordance where the genotype and the phenotype are matching is really powerful evidence to start moving that variant. But it's interesting, right now, most genetic counselors will, and most genetic companies will say this VUS should not be tested through the family. And I've always been puzzled by that, and I honestly disagree with that approach, because I think tracking a VUS through relatives who show the phenotype is really, really helpful to try to move the needle on how that gradient gets classified. Now if you don't have anybody good to track it through, right? If you've done the echo or the MRI and nobody else shows exhibit A of apical cardiac hypertrophy, then the presence or absence of that variant in any of those relatives doesn't help you much. Okay. So it really depends, but I actually find, and this is where genetic counselors and myself and other genetic cardiologists, we respectfully disagree with each other a little bit, because I think testing relatives for a VUS when the phenotype is there in other relatives is an incredibly helpful exercise. So let me follow through on that. So let's say you do test them and they don't have it. So it's almost kind of a double, here's my concern. If this person really is at risk for the disease and you've got, in a sense, a false marker, I mean, I understand it may not be a false, let's just argue that maybe it's a false marker. I then use that to test a couple of family members and I proudly tell them, you don't have this VUS. Is that okay? Because if that VUS really wasn't what was responsible for the phenotypic problem that my patient has, then maybe we don't follow up on them and maybe that's a bad thing. So how do I get out of that conundrum? Well that's a mess and we're finding people in that mess all the time because they've made a premature judgment call on that VUS. So if you take a VUS and you incorrectly operationalize it as the cause and it's not, and you dismiss people who don't have it because they don't have it, well, you've dismissed them for something that's irrelevant. Right. That's my concern. And so that's why you really have to commit yourself as the clinician and say, this variant is clinically actionable such that if it's there, I keep that person, that family member, that relative in the queue and I continue to follow up and risk assess whether they are starting to manifest the phenotype or not because it is the disease-causing variant. On the other hand, if I didn't even think or I wasn't even convinced that the VUS was the cause, then I better be really, really slow to dismiss somebody who doesn't have it and I better keep them in the path as well, the path of reassessment. And so we're starting to see this, Eric. We're seeing pathogenic variants that over time get demoted. And now we have to recontact and say, you know, the variant that we were prosecuting the family on is kind of been now judged innocent instead of guilty. And we've had it the other way where over time, a VUS that somebody thought was ambiguous and they thought they were stuck, the company eventually mounts enough evidence minus the phenotype to where on in silico tools, they now say this variant has now received a variant upgrade. So always keep the families in the stay tuned box that there are many variants that you can absolutely bet the ranch on and it is a disease variant 20 years ago, it's going to be a disease variant 20 years from now. There are others, not very many, but there are others that were graded as pathogenic that they were called guilty, but years later, the charges are reversed and you're now dismissed as innocent or uncertain. And then there are still those that in the VUS land where you and I can promote some VUSs out of genetic purgatory in a split second by the power of the phenotype, whereas others, especially VUSs in a minor gene, they stay stuck for a long, long time. So it sounds like unlike some things where there's like, it's there or not there, this VUS mess, if I may call it that, really demands that the clinician stop, take a deep breath and think through all the points you've raised, right? How strong is the phenotype? Is it in a gene that is a major gene versus a minor gene? So it really isn't a slant, it isn't really like a one stop shopping. You really, it sounds like you have to apply a fair amount of finesse. You do. And you know, genetic testing never was and never will be a binary test altogether. Yes, no, yes, no. Sometimes it's yes. Sometimes it's no. Sometimes it's maybe. So genetic testing has sort of well joined a lot of other tests that we are familiar with in cardiology, like the 12-lead electrocardiogram, where we still have a lot of people who remain QT challenged after a hundred plus years of Eindhoven, where they have some QTCs that are slam dunk wrong, others that are well normal, and others that were so grossly mismeasured by either the computer or the person that, you know, even that test has ambiguity, has a finding of uncertain significance. And genetic testing sort of joins a test, the ECG that all of us are well familiar with, but we sort of give the ECG a pass. And we as clinical cardiologists tend to be a little bit too harsh on an ambiguous result in the genetic testing realm when we're not as harsh when it's on one of our own tests that's been in our own backyard for a century. Well, you may be right. I tell you, I think you have to be careful with both. I mean, because I see a lot of ECG mistakes too, but I know we have a stop point. Michael as always, great information and thanks everybody for listening.

variants of unknown significance

genetic testing

phenotype

clinical presentation

co-segregation data