Genetic Testing in EDS with Dr. Paldeep Atwal (Ep 112)

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Dr. Linda Bluestein: [00:00:00] Welcome back, Every Bendy Body, to the Bendy Bodies podcast with your host and founder, Dr. Linda Bluestein, the hypermobility MD. Today we'll be talking to geneticist, Dr. Paldeep Atwal. I am so excited to talk to Dr. Atwal again after Our last conversation that was about four and a half years ago, Dr. Atwal and I have a couple of patients in common and we're going to hear about one particular case that's so interesting because the patient presented really looking very much like they had hypermobile EDS, but Dr. Atwell did genetic testing on this person and discovered that they actually really had a very rare type of Ehlers Danlos Syndrome, or EDS.

So genetics is so important, it's so complicated and so nuanced, [00:01:00] so this is going to be a really important conversation. Dr. Atwal is a board certified clinical and medical biochemical geneticist. He formerly served as Mayo Clinic's medical director for the Center for Individualized Medicine and clinical lead for the Department of Clinical Genomics at the Jacksonville campus.

Dr. Atwal's clinical interests include undiagnosed diseases following lengthy diagnostic odysseys and inborn errors of metabolism, including mitochondrial diseases. Through his work, he helped discover two new genetic connective tissue syndromes that result from defects in the FLNA and AEBP1 genes and has published extensively on human genetics with over 100 publications to date.

Genetics is a very exciting and very fast moving field. So this is a really important conversation. As always, this information is for educational purposes only and is not a substitute for personalized medical advice. Stick around until the very end, so you don't miss any of our special hypermobility hacks.

Let's get [00:02:00] started.

Okay, I am so excited to be here with Dr. Atwal. I spoke to Dr. Atwal back in episode eight, uh, called Demystifying Genetics. That episode was released over four years ago. So in the world of genetics, I'm sure a lot has changed since then. Am I correct about that? 

Dr. Paldeep Atwal: You are. And I can't believe that was four years ago.

Wow. That's so long ago. 

Dr. Linda Bluestein: It feels like 

Dr. Paldeep Atwal: maybe, maybe two, but not four. 

Dr. Linda Bluestein: Right. Right. Uh, actually Rob looked it up for us. It was actually four years and four months ago that the episode was released. So we had the conversation of course, before that. So it's pretty crazy to think that. 

Dr. Paldeep Atwal: It is really crazy.

That's, uh, Yeah, 

Dr. Linda Bluestein: for sure, for sure. So I, I just am so excited to chat with you. Of course, so many people have questions when it comes to genetics in this, in this space. So this is such a super important conversation and maybe you can start by giving us a little genetics [00:03:00] 101. Right. So, 

Dr. Paldeep Atwal: you know, when you think genetics.

We really understand genetics very intrinsically. And when we start giving examples such as, you know, why do we look like our parents? Right? And why do we have this similar hair color, eye color, skin color, all of these, all of these physical features. And we know what genetics is. And it's these kind of units of hereditary, if you will, that are passed down from one generation to another.

And And it's what makes us, um, look, look at what we do, think, think how we do and, you know, grow and develop and normally, and so most of the time, you, you think genetics, but you think DNA, right? So DNA is the smallest piece of genetic material. It's housed in chromosomes. And then those chromosomes are what's in your cell that really tells your body how to grow and develop.[00:04:00] 

Now there's, there's a very simple 46 pairs of chromosomes. It's surprising for some people to learn that chromosome 1 to 22, They're numbered based on size, right, so there's nothing, nothing, nothing more complicated than that, it's just how big they are. People think there's some weird, uh, interesting formula to figure out which Y is the scroplum number one.

It's just because it's the biggest one, and the 22 is the smallest, and then X and Y, the 23rd group, Two X's, you're a female, and having a Y chromosome means you're male. And really, that's the basics of genetics. Obviously, there's much more to that that we'll talk about, I'm sure, but that's the basics. 

Dr. Linda Bluestein: And of course, we're going to talk about hypermobile EDS today and related conditions, um, because we know that there's a lot of differences, right, but there's also a lot of phenotypic overlap.

So, could you explain what phenotype and genotype [00:05:00] are and why that's important? 

Dr. Paldeep Atwal: Yes, so phenotype is, if we turn the word around a second, it's type of genes, so you have, uh, it's what version or what, uh, what type of gene do you have at that particular, of that particular gene, and then the phenotype, you know, is, uh, is a gene.

is the term used to describe the actual physical clinical presentation and someone. So we need to use the term phenotypic expression. It's a expression of the findings in a physical way. So the, if the gene, let's say the genotype causes, think of something ridiculous like green hair, right? And then the phenotype would be green hair, right?

And so if you don't, and so the phenotypic expression of that genotype. And then maybe another one that causes, you know, bright blue hair. And so you'd [00:06:00] have, uh, you'd have a phenotypic expression based on that genotype. We use the term, we use those terms together in what's called genotype phenotype correlation.

So, and that's very important when they cholera, cholera, uh, uh, correlate, but also when they don't cholera, uh, uh, uh, correlate. So if your genotype says you have You're supposed to have blue hair and you don't, and you have blue hair, great, they're correlated. But if it doesn't, that's also interesting. So what happened?

Right? And so when it makes sense, it's useful, but also when it doesn't make sense, it's useful as well. But that's the difference between genotype and phenotype. 

Dr. Linda Bluestein: So, that's really interesting. So, you're saying that sometimes you can actually look at the genotype, or like you said, type of gene, and you expect to see a certain type of phenotype from that genotype or the expression of the gene, and it doesn't correlate.

It doesn't correlate like you would expect it to. Okay. 

Dr. Paldeep Atwal: This happens regularly in my world, of course, because we have, let's say we have a [00:07:00] genetic binding. Uh, the, the lab isn't too sure about. So it's my, my role as the clinical geneticist to look at this and say if it's clinically meaningful for that patient.

So I'll look at the genetics and look what is expected to happen, right? Uh, uh, I'm gonna try and use a different analogy than, than hair color . But, uh, but let's, you know, let's say, you know, a certain thing is supposed to happen in the, in the, in the, in the body based on that clinical, uh, that genotype and.

The term we use, and you're obviously familiar with this as a physician, is clinical correlation, right? So is there clinical correlation or is there phenotypic expression of that gene or that genotype in the patient? So for example, I'll see, this happens a lot often in Ehlers Danlos, I'll do a large panel and then they'll find a variant of uncertain significance and one of the genes in that panel and the gene is responsible for a very severe skeletal dysplasia that's obviously manifesting in from childhood.[00:08:00] 

And so the patient naturally is concerned, you know, what does this mean? Is this, is this, you know, do I have this? I looked it up, it looks horrible. All of the, all of that is normal, right? So, so you look at it and I'll explain, you know, that this gene causes this condition, and this condition, it's obvious from birth that you have these findings, and these will be the findings, and they're sitting there 40, 50 years old, or 30, whatever they are, and not having any of those symptoms.

So they don't have clinical correlation. And they're not going to get clinical correlation all of a sudden from a condition like that. You're going to have it at birth. So, I tell them, you know, there's no clinical correlation here, there's no genotype penotype correlation, and therefore you don't have to worry about that.

Dr. Linda Bluestein: Okay, so that's really, really interesting, and we're going to for sure talk about variants of uncertain significance, and we are definitely going to talk about, Uh, some real challenges in this space, like direct [00:09:00] to consumer testing, and people who don't have a clinical geneticist like you on their team, which is really challenging, right?

So probably a number of people are going, wait, what? I didn't think that you could have a genotype and not have the phenotype. So how, how could that possibly work? Yeah. 

Dr. Paldeep Atwal: I think most of the time we think a single gene change when you have, you expect it to have the phenotype of that. 

Dr. Linda Bluestein: a 

Dr. Paldeep Atwal: gene change. So let's say you have a disease causing or pathogenic change in a gene.

So that's the genotype, right? Uh, and you'd expect the phenotype to be whatever disease that was, right? And that's, you know, that there's, there's, that's pretty clear, right? And it may be surprising for some people, uh, that that happens in some conditions that happens all the time. So for example, if we take a condition like Huntington disease, a neurodegenerative condition, If you have the genetic change that causes that [00:10:00] condition, you're going to get the condition.

It's only a matter of time, right? Now, contrast that with something like hemochromatosis, a condition of iron overload in the liver. You can have, uh, the genetic, uh, gen, uh, gen, so you can have the genotype for hemochromatosis, meaning two abnormal copies of the HFE gene. Only 5% of the time though, you actually have phenotypic expression of full true hemochromatosis.

So therefore, or 95% of the time you have the gene genetic change, but you don't have hemochromatosis at most genetic. Conditions are somewhere in between 

Dr. Linda Bluestein: that. 

Dr. Paldeep Atwal: And people are quite rightly will ask, well, why, this doesn't make any sense. It doesn't make any sense in isolation, but those genes do not live in isolation.

Those genes live amongst 20, 000 other genes that are having interactions and relationships and effects on each other. [00:11:00] And so that's why sometimes it occurs like that, and sometimes you don't see the condition. We're only starting to figure out the complexities between these gene gene relationships.

Interactions like that. What we really practice currently in medical genetics, for the most part, is Mendelian genetics. They were named after Gregor Mendel, the, you know, the, the, the, he probably learned about them in, in, in the high school biology textbooks, so the peas and dominant and recessive inheritance, uh, where a single gene or a single trait is passed down in a certain fashion.

Uh, and, and that's, you know, that obviously is true and we, we see many conditions like that. But there's much more to genetics that we're only starting to uncover. Complex traits, complex disease genetics, gene gene interactions and so on and so forth. 

Dr. Linda Bluestein: Wow, that's really fascinating and I like that you gave two examples that are really on opposite ends of that spectrum.

I think that's, those examples, I think really help to illustrate the challenges that we can [00:12:00] see in genetics and um, so that's really, really fascinating. Wow. Okay. I, I kinda, that kinda surprised me to be honest. I didn't realize that like with hemochromatosis that you could have two abnormal copies of the gene and that only 5 percent of people would actually get hemochromatosis.

I did not know that. 

Dr. Paldeep Atwal: Yeah, it's really, it's, it's such a common trait that, um, you know, thankfully that's the case. 

Dr. Linda Bluestein: Right. Right. So, so what about, okay, you gave those two examples, right, for your opposite ends of the spectrum. What about the inheritance patterns for the, we'll, we'll put maybe hypermobile EDS aside for a minute.

Cause of course we don't know the genetic. I don't have a marker for that yet. But for the other types of EDS, where do they fall in there, do you think? 

Dr. Paldeep Atwal: So most other types are dominant, there are some recessive, but most are dominant, meaning you need one abnormal copy of the gene to manifest. 

Dr. Linda Bluestein: And 

Dr. Paldeep Atwal: That being [00:13:00] said, even within a family, let's say, a family of classical EDS, a family of vascular EDS, or something like that, you'll, you'll see a spectrum within the family.

So you'll see it, you'll see it manifesting. Generally, if you have Generally, the genotype phenotype correlation is high, meaning that if you have the gene changes, it's highly likely, so much closer to the 100 percent side of the spectrum that you're going to see changes. And just to clarify, since we're really diving deep into genetics here, to clarify, another way of thinking about this is two genetic concepts, they're often confused.

And I think it'd be great to have an explanation from a geneticist on this, and it's very important when we understand this, and I explain this to patients all the time as well, or try to at least. So there's the concept of lack of genotype phenotype correlation, you could [00:14:00] think of it in another way, of incomplete penetrance.

And what do you mean by that? So incomplete penetrance, meaning. The gene does not always manifest the disease, so it's an incomplete penetrance into the physical spectrum or the clinical spectrum, what you actually see in the patient, right? Now, that's different to a similar but distinct genetic concept of variable expression.

So, you can have a gene that, let's say in the same family, same gene change. Yet, sister is more effective than brother, or brother is more effective than sister, or something like that, right? Or parent is more effective than child, or vice versa. Now, it's the same gene, but yet, in one individual, it's more affecting them more.

The phenotype is more severe. Let's, let's say that, let's say it in a medical context than the other. Now, that term is called variable expression. [00:15:00] Now, so they're both, it's penetrant in both, but it's, one person maybe it's milder, and let's say the other is much more severe. So, yes, they both have it, but one has it much more than the other.

There's layers and layers to these things, right? 

Dr. Linda Bluestein: This seems like that also makes it really hard for a condition like hypermobile EDS to find the gene or genes that might be responsible. 

Dr. Paldeep Atwal: Absolutely. And I think there's actually clusters of people within hypermobile EDS that are distinct in their own way.

Dr. Linda Bluestein: You 

Dr. Paldeep Atwal: know, you see people that tend to have severe. Disautonomic features, thoughts, GI motility issues, gastroparesis, temperature dysregulation. And in some, some individuals I've seen, the disautonomic features are their most challenging part of their, their disease burden. [00:16:00] More than the joints. Right. So sometimes significantly more.

Dr. Linda Bluestein: Mm-Hmm, . 

Dr. Paldeep Atwal: And then, then there's, then there's some individuals or subset. It's really the mast cell issues. Mm-Hmm. . And some don't really have mast cell issues. Right, right. So we've got distinct groups within the group. The group. Right. So, and you see that in, you see that in many conditions. Right. That's not, that's nothing new.

Uh, but it's, I think that a lot more work needs to be done to characterize that. 

Dr. Linda Bluestein: Yeah. And that, that paper, I'm trying to remember if you were one of the co authors on that paper about phenotypic clusters that came out recently, and I think they identified like three or four different, do you remember seeing that?

Like three or four different clusters? I was involved in that. 

Dr. Paldeep Atwal: Yeah. Yeah. Yeah. But I agree with what they're saying. It's very true. And you see, I see it in clinical practice every day that there's absolutely phenotypic clusters. And maybe tier 4 is a good start. Maybe that's accurate. Maybe it's more.

We're just starting to look at that. 

Dr. Linda Bluestein: Yeah. Some had a more predominant mast cell [00:17:00] picture, like you said, some had a more predominant like neurologic picture, um, et cetera. That could be gene gene interactions, influence of the environment, um, incomplete penetrance, variable expression. 

Dr. Paldeep Atwal: All of those phrases.

You got all the buzzwords in there. 

Dr. Linda Bluestein: Yeah. I just thought I'd just throw that all in there, you know, make a little soup out of it. 

Dr. Paldeep Atwal: Which is what it is. That's what it is. Yeah. 

Dr. Linda Bluestein: Yeah. Yeah. Wow. Fascinating. Fascinating. Okay. So when it comes to the inheritance of hypermobile EDS? Can we really actually say anything about that if we really don't know what the genetic marker is?

Dr. Paldeep Atwal: That's a great question. And the answer is we can based on if we take a step back and think historically, prior to the ease and advent of large scale molecular genetic testing, if you look at the geneticists before my generation, They didn't have access to genetic testing. They weren't sending exomes.

They weren't doing 50 plus [00:18:00] gene panels and getting them back in a couple of weeks. They would maybe have access to a single gene they could test for if they're lucky. Or not. Or they didn't know the gene. So we had these big textbooks of human malformation that we had to learn through training and we had to review and look at.

And you would look at these textbooks for patterns. And then there was this, we use this resource called Mendelian inheritance in man used to be a textbook. Now, now it's online, right? So, 

Dr. Linda Bluestein: so 

Dr. Paldeep Atwal: these are catalogs of different syndromes. And so you're once you identify someone has one of these You can follow what happens in those families over generations, and you can see it is recurring in that family in a certain pattern.

Now we know different [00:19:00] patterns, different inheritance patterns. For example, if you have generation to generation, That's different to only siblings being affected and no generation to generation, 

Dr. Linda Bluestein: so, 

Dr. Paldeep Atwal: um, and so we see it's generation to generation, and we also see the hallmark of dominant inheritance, uh, which is male to male transmission.

So a father can pass, uh, on to a son. Now, if that, if that, that doesn't happen in X linked inheritance, right, and that doesn't happen in mitochondrial inheritance, that obviously doesn't happen in recessive inheritance. So, so because of those features that have been documented and described throughout, uh, the past two decades of, of describing these, uh, LRS downloads, HyperMobile and other types of LRS downloads, we know it's, it's dominant and appears.

Now, that being said, Back to the point you made earlier on phenotype, genotype, phenotype, sometimes the [00:20:00] expression is highly variable, I mean often actually, the expression is highly variable within a family such that it's questionable whether someone even has it. And I get this question all the time from patients, well how do I have it?

My parents aren't affected. I get that question all the time, and it can be quite challenging, and I think it's even more challenging now because we're used to every genetic condition having a gene that we can test. 

Dr. Linda Bluestein: But 

Dr. Paldeep Atwal: that's like the normal, which is a huge testament to the success of genetics, like you said, four years since we did this podcast.

You know, that's like, you know, 15 years of med in medicine in terms of genetic advancement, right? Mm-Hmm. , right. And so we're al already the genetic practice, my genetic practice has changed four years ago until now in terms of what testing we're doing, what genes we're looking at. 

Dr. Linda Bluestein: Mm. 

Dr. Paldeep Atwal: And it'll change another four years.

So we're really rapid to think about the rate of change of common [00:21:00] clinical practice. 

Dr. Linda Bluestein: I think maybe we should book our next interview now in a year instead of in four years.

And when it comes to hypermobile EDS and then we know that HSD is We have the 2017 criteria for hypermobile EDS, and then if you have symptomatic joint hypermobility, but you don't meet the criteria for hypermobile EDS or have another condition to explain your symptomatic joint hypermobility, that's, that's the current definition of hypermobility spectrum disorder, correct?

Right. That's correct, yeah. So, you know, some people, you see people saying, well, but are these really the same condition? Are they, are they different? Um, what are your thoughts on that? 

Dr. Paldeep Atwal: Yeah, I think, I think when it first, I think we need to do better with the criteria. And, you know, we need to look at a more holistic view of what's really affecting people in terms of clinical criteria is probably not [00:22:00] enough when it comes to, well certainly not enough in my opinion, when it comes to the dysautonomic features and other mast cell involvement, those kind of things.

We're not really adding enough of that. I also never like the idea of a very complex diagnosis. You know, genetic conditions with multiple overlapping areas and multiple systems involved simplified down to ticking a couple of boxes and A's, B's and C's, right? And if you, I think, you know, it's hard to do that.

And I think it's, it's not to say it's not, it's not useful. It is useful. We have, if we do that, we miss things, right? And I think with the hypermobility spectrum, It's, it's not my favorite term to use, if I'm honest, I think there's, there's problems with labeling people hypermobility spectrum, uh, without giving them, it's, you know, it's, I think people feel a bit in limbo with that diagnosis, and I, [00:23:00] I tend to try and not do that and look, look, you know, look one way or the other.

There's also, just on that note, I don't want to make a tangent, so bring me back if you need to. There's also a group of, a subset of patients that I've seen that it's very interesting. They're not hypermobile, yet they have all the other features. POTS, GI motility, mast cell, temperature, even kind of bruising issues and other skin manifestations.

But they're not hypermobile. 

Dr. Linda Bluestein: But they 

Dr. Paldeep Atwal: have joint pain. So I think there's a lot more work we need to do to figure out these different groups. And there's likely many categories we don't even realize that are there. 

Dr. Linda Bluestein: Yeah, I definitely have observed that as well. And sometimes it's really challenging because since the criteria start with, you know, generalized joint hypermobility and since we [00:24:00] don't have a lab test for hypermobile EDS at this point in time, but it seems like, I don't know, I don't know what your thoughts are in terms of prevalence.

Of course, we don't have good data. I'm gonna put you on the spot and ask you if you were to take a guess. And we'll, we'll come back in like four years and we can look back at this episode and say, okay, how close were you? Um, if you were to take a guess, what would, what would you, what would you think?

Dr. Paldeep Atwal: Well, can I qualify my, answer? I'm going to call an educated guest, with some history. So there's another genetic condition called Fabry disease, it's a lysosomal storage disorder, and prior to the advent of molecular genetic diagnosis. There was a, I don't recall the numbers, but there was a, let's say it was, you know, let's just give an example, one in a million, right?

And then, um, we were able to test for it genetically. And then the [00:25:00] biggest thing that came was a treatment for it. Once that started, sorry, it was already being able to test it for, but no one was interested in testing because there was no treatment, right? So, uh, there was, uh, once there was a treatment, everyone started getting tested for it.

And then more, then suddenly the prevalence. The incidence, uh, became much, much higher, right? So it's from one in a million to one in, let's just say, I can't, again, can't remember the numbers right now, one and a half a million. And then, uh, it started, then it was put on newborn screening in certain states.

So now we're looking at every child at birth. So the numbers have dropped, you know, thousand fold in magnitude in terms of prevalence. And I think if you look at historically what people thought about hypermobile LSD amylose, Something similar may happen, and that I think the true prevalence is closer to one in a thousand, maybe even less than, [00:26:00] um, so we're on, on par with things like, um, uh, type 1 diabetes, right?

It's much more common than we, than we realize, and very under diagnosed, it's very under recognized. It's a specialty, the specialty for the diagnosis is mainly medical genetics, but most geneticists reside in children's hospitals, they don't see adults. Many patients of Manifestor are already in adulthood, 

Dr. Linda Bluestein: so 

Dr. Paldeep Atwal: we, we have these compounding problems leading, and there's hardly any geneticists in the country to begin with, and this is just the US, and I see patients all over the world, and they don't have a geneticist in their country.

to even make a diagnosis. And I'm talking, I'm not talking about small countries. I'm talking about Big, you know, billion plus population countries that are struggling with these issues. And so we, um, I think there's for all those reasons that I mentioned, I'm going to say much closer to 1000 or less. [00:27:00] 

Dr. Linda Bluestein: And when you say or less you mean that Oh, sorry.

Dr. Paldeep Atwal: Or 1 Right, 

Dr. Linda Bluestein: right, yeah. I just wanted to make sure that that I understood to make it clear. Yeah. So, and so, uh. Thank you for 

Dr. Paldeep Atwal: clarifying. 

Dr. Linda Bluestein: Yes. Yes. Of course. Of course. Okay. So we're going to take a quick break and when we come back, we are going to cover a bunch of other fantastic genetics topics with Dr.

Atwal, including direct to consumer testing. So we'll be right back.

We are back with Dr. Atwal. I'm so excited to chat with you some more about genetics. EDS and all of these complicated genetics that I, I think nowadays part of the confusion is, you know, you can, you can just shop online, like you're shopping for clothes, you know, and, and purchase your own genetic tests.

And I think that people might really be blown away by the first part of this conversation. At least, at least I feel like I am, you know, that. to realize that there are some conditions where, whether it's variable expression, incomplete penetrance, gene gene [00:28:00] interactions, that, you know, A doesn't always equal B.

Dr. Paldeep Atwal: Yes, and I think as well, it's the quality of Good testing in question. I've worked and helped with a number of companies looking to facilitate genetic testing, 

Dr. Linda Bluestein: uh, 

Dr. Paldeep Atwal: with, which is great. And that's, that's very good, good thing to facilitate it. Now in that capacity, we all, we almost came, became like a mini regulator.

So we would only look at supporting tests if they were clinically valid and clinically meaningful. I think that the average. Member of the public would think if a test is available, there must be some good legislation, you know, regulation that has gone through to ensure that it's clinically relevant, clinically meaningful and has clinical utility.

Now, they may be surprised to hear that that's actually in some cases that's not the case. For example, I remember in that capacity I had a [00:29:00] a test come to me that they were offering genetic testing to see what position in a football team you would be best at. Are you serious? Yeah, I'm serious. I'm serious.

Yeah, I'm serious. So, yeah, they're, they're, I don't even, I didn't even look at it. Uh, I mean, I, I looked at it, of course, but, uh, obviously this is nonsense, right? And they're, you know, taking the other thing that people look at is you take. odds ratios and try and apply them to create big big effect sizes when they don't exist.

For example, and this is another thing that it's difficult to to explain, but when you explain it in this fashion it's not, if someone tells you your risk of something doubles, Uh, well, usually that's, that's kind of alarming, right? There's some risks I doubled off. And if it's a cancer or something else, then, um, you know, then of course, more, [00:30:00] more, more alarm.

Now, if I, if I, if I told someone, look, your risk of this particular rare cancer is, I don't know, one in, one in 10 million. And they say, okay. And I said, and I now say, now your risk, by the way, is one in 5 million. No, that's not really a meaningful change to me. I don't know about you, but it's not really a meaningful change, but I could also say your risk is doubled for this.

Right. And so I think taking things into context, uh, is critical. And, and so that's one thing with that testing. The second is, uh, you know, I talked about quality. There's quality in all aspects of the genetic test process, just like any other test process. There's the quality of the collection. There's the extraction of the DNA.

There's quality control in that extraction to ensure there's enough [00:31:00] quality good DNA to be able to run and run a, run the report. Then there's the actual quality of the sequencing. The sequencing, for the most part, is actually generally done well by most labs. It's very standardized, often on the same platforms.

The biggest issue comes after the sequencing and interpretation and sign out of the findings. The human genome is very much like reading kind of hieroglyphics, in the sense that the seeing it as the easy part, like you can, like, we all look at it, but to understand what it means is the complex part, right?

And so that the understanding is really the challenge. And creating clinical relevance in that understanding is even a second challenge. That part is really the hard part in genetic testing. And that's actually the part that takes a lot of time and effort and skill [00:32:00] by lab based molecular geneticists and molecular pathologists and other specialists.

So, that being said, offering a sequence of And then having, you know, giving you kind of a very rudimentary filtering algorithm to kind of play about with on your computer is not good in terms of quality interpretation. And I see, I get these reports sent to me all the time, almost every day, at least every week.

And there's hundreds and hundreds of red light variants.

I call it the, um, the traffic light sign, right? So whenever you see a test that qualifies your genetic rapport or the variance, and you know, red, yellow, green, or each one, I'm not saying it's wrong, the test is bad, I'm not saying that, but I'm saying [00:33:00] that's a bit of a red flag, just be cautious, proceed with caution.

And, uh, you'll often see that, that the, the, the, the traffic like saying in many of these poor, uh, uh, not very accurate reports. 

Dr. Linda Bluestein: I see that all the time. I just, I just saw, I just saw that yesterday, literally, literally, uh, somebody brought, brought me their, their report. So that is really interesting. I feel like, like you said, we think that if it's being allowed, it's must be allowed.

Um, like you said, regulated, um, in some way and be high enough quality information. And then if we get a report back and it says that we have, you know, certain genetic markers for things that now it's in writing. And especially if it's like you said, got the red light, green light, yellow light, it is hard to think, 

Dr. Paldeep Atwal: yes, 

Dr. Linda Bluestein: it might not be accurate.

Like that, I feel like, 

Dr. Paldeep Atwal: yeah. So, let me give you an example. So, I, [00:34:00] and this is not one isolated incident. I've seen this a number of times. So, let me just give you this example because it's the scariest example, if you will, or one of the So, a patient thinks they have Ehlers Danlos. They researched online.

They looked at it all. They decide to order a, you know, one of one a test by the by themselves, which in a, in a, with a test, they and good conscious think this is the right test. This is a good test, right? Uh, and, and so they order the test and it comes back. They have, uh, uh, a pathogenic variant and call collagen D or call three A one for vascular ds.

Now they're freaking out, 

Dr. Linda Bluestein: right? 

Dr. Paldeep Atwal: I I, yeah, they, they're either, they're worried that, oh, I have, you know, I thought I had hypermobile, but now this testing have vascular. And so they're worried, and you know, they're worried about them, they're worried about their kids, they're worried. So the next thing, they eventually make an appointment to see me or another geneticist.

And I'll look at them, I'll do a [00:35:00] proper history, clinical assessment, there's some facial features that you can see and other features. You don't have them, but what am I supposed to do? They have this report saying this variant, right? I look the variant up, uh, and um, you know, the variant is actually, there's actually two scenarios that can happen here.

So let me tell you the first scenario when I look the variant up. First scenario is the variant by every other, let's call it, let's say reputable clinical lab. It's reported as non disease causing. So there's, you know, even looking up in ClinVar, right, ClinVar Clinical Variation Database, uh, all of the, I don't, not necessarily name labs, but good clinical grade labs, let's call them, will, will report their interpretation of that variant when they've seen it, as and when they've seen it.

And so if all of them are saying it's benign, and this lab is saying it's disease causing, well, I'm not, I'm going to trust the clinical grade labs over this lab. So I'll say that to the patient. [00:36:00] Hopefully that reassures them. They've also gone through a lot of psychological stress. A huge amount of stress at that point, unnecessarily.

The second scenario is the variant that has been found. is, uh, is disease causing in ClinVar and, and, and as reported by the other labs. So the variant is known to cause disease. So what I'll say in that point is, look, let's check if you truly have this variant by a clinical grade test, right? So I'll order a test from a lab that I would feel comfortable standing behind those results, 

Dr. Linda Bluestein: right?

Dr. Paldeep Atwal: Because currently I'm not comfortable standing behind those results, right? And so, and the test will come back negative. And, and, and just to be clear specifically, I'll ask the patient, the, the, the patient, sorry. I'll ask the lab. This is, I'll send you another report too. . Mm-Hmm. . This is the variant that you must look at of, [00:37:00] of all the variant.

Of course, we can look at the whole gene of all the variants. This is the one you need to look at. And I say, know that wasn't there. It was the wild type variant. It was a normal variant. And this has actually happened. 

Dr. Linda Bluestein: This is like multiple times. Really? Yes. Wow. Okay. That's, that's scary. Cause I mean, people are going through incredibly stressful things.

Like you said, we have a shortage of geneticists, so some people can't get in to see a geneticist and maybe they're, so therefore they're doing, they're purchasing testing online and they may make decisions about having a family or not having a family based on that information. 

Dr. Paldeep Atwal: It's frightening. Very frightening.

That's, uh, that, you know, when it comes to. Things like family planning, recurrence, all of these things, that's when, that's when you really start thinking. We have this thing in genetics, we don't just treat, we don't treat patients, we treat families. Really that's what we do, we're often, it's, you know, the person's [00:38:00] there ostensibly for themselves, but actually, when you really get into it and start talking about family history, they'll tell you, look, I actually have three kids, and I'm starting with me, but I'm really more concerned about my kids than me.

Dr. Linda Bluestein: Yeah, 

Dr. Paldeep Atwal: so they're really interested more about family rather than, or interested about family rather than just themselves. And so that, that's what we deal with all the time in genetics. We're the con. That's our, the nature of genetics as, as we said at the start, is, you know, we look like our parents. We look like our, our fa our family.

So why, why do we do that? And that's, that's , that's genetics in a nutshell. 

Dr. Linda Bluestein: So if someone can't access a geneticist, um, you know, I mean, I obviously evaluate people all the time for hypermobile EDS and related conditions. And I have obviously a very different background than you have as an anesthesiologist.

And I'm much more focused on people's pain, but especially if they're really, really concerned about vascular EDS, or if I find some other indicators, then I, then I will order genetic testing from, like you said, a clinical lab. I will, 

Dr. Paldeep Atwal: I 

Dr. Linda Bluestein: will do, I [00:39:00] will do that for people when I feel that it is appropriate, but yes.

What else do you think people can do if they can't get in to see a geneticist? You know, maybe they can't get in to see me or somebody like me who does, you know, do some amount of genetic testing even though we're not a geneticist. So my ability to interpret the information is going to be less. What do you think that person should do?

Dr. Paldeep Atwal: So there's a couple of options. Let's just try and explore this. So first, as There's the standard medical model where patient goes to the doctor, doctor decides what test to order, and orders on behalf of the patient. And that's, we're all used to that, we don't need the explanation of that. Now, I will not say, I won't say recently, because it's not that recent, but direct to consumer testing where you can go and buy a test yourself and have the results of that without physician involvement.

And, you know, we just talked about some of the pitfalls that can happen with that. Not to say it's all negative, by the way, just to be clear, right, it's not all [00:40:00] negative, but, uh, the second, but there's a, I won't call it a sub element of Direct to Consumer, I would call it a third option, if you will, whereas there's these sub elements.

patient initiated or consumer initiated testing, where they, there's, there's companies out there that you can go there, go to the company and express an interest in this test, let's say a connective tissue gene panel or something like that, and they can either help facilitate with your own doctor or they can use one of their doctors.

to review the appropriateness based on some sort of questionnaire they might give you or something some other mechanism and and say yes this is appropriate for you and you know you'll pay for the test and then they also provide follow up and and whether it's with a genetic counselor whether with with the physician themselves or someone with knowledge to interpret that result because as you As you know very well, the results for genetic testing is [00:41:00] challenging.

I regularly have patients, when we do the connective tissue gene panel, for example, I regularly have patients say, well wait, so does this mean I don't have hypermobile ADNs? When it comes back negative. And then I have to explain, We haven't found the gene for that subtype, we tested for all the other subtypes to make sure you don't have something that can cause vascular fragility, aneurysms, all of those things.

We don't, we want to make sure you're not a risk for them. And so then they understand that, no, it's not, I'm not saying we don't have, it's actually helping us to reconfirm we have that. because we looked at these other things that can be similar in presentation, have overlapping phenotypes, going back to the phenotype word, but ultimately significant potential life threatening differences.

That's why we did the test in the first place. Just to have that discussion and explanation why you're doing the test is really necessary I think for someone. It's not [00:42:00] easy to navigate such a complex world of genetic testing, even for a top position like you, it's hard. So, I think for the patient to do it themselves, it's very challenging.

Dr. Linda Bluestein: It's very, very challenging. And I have ordered, you know, like you said, there's specific panels, right? And then we can do whole exome sequencing. We can do whole genome sequencing. I've ordered a whole exome sequencing before for a couple, actually one of them as a patient that we have in common. And shockingly, it came back with one word, negative.

And this person. Yeah, I was shocked. I was absolutely shocked. Um, so I guess in terms of what panel to order and when, when it comes back with that one word negative, but people do have variants of uncertain significance, I guess, do they report it that way? Because the variants of uncertain significance, none of them are clearly pathogenic.

Um, or I guess, what are your, what are your [00:43:00] thoughts on, on that? 

Dr. Paldeep Atwal: Right. So, so the labs, they all have a slightly different structure, how they report things, but in general, they'll see. Negative. Some will say negative when, when there's, you don't find any pathogenic variants and any, uh, variants of uncertain significance.

Some will say negative only if you don't find any. There's no pathogenic variance, but, um, but if they find variance of uncertain significance, they won't see negative, they'll see intermediate or unclear or something like that. And so they'll qualify that with different categories of result. And there's a whole counseling on genetic results that you go through the different categories, pathogenic variance related to their phenotype, pathogenic variance unrelated to their phenotype.

So You're testing someone, you're doing an exome or someone with EDS, but then you find out they have, you know, uh, cardiomyopathy that isn't related, right? And then [00:44:00] there are unclear variants related and unrelated to their phenotype. And then often in these tests, there's the American College of Medical Genetics.

And this, uh, reportable variants that they like to have in the BRCA genes, other ones that, if you're looking at someone's exome or genome, then they recommend you find a disease causing variant, and one of them you should let the patient know, or you should offer, and usually the patient has to consent into that before you do the test, right?

And then now, some of the labs are now doing, offering pharmacogenetic variants in addition. So now you've got all these pharmacogenetic variants, so the exome or the genome becomes this huge complex. Just to go, even if it's mostly or all negatives, it's a hugely complex thing that takes, takes a long time.

So how do you scale that discussion to ensure, one, the patient understands what happened and two, you have enough time to do that for, for all patients getting genome sequencing? Because it's only increasing, [00:45:00] as the cost is going down, as availability and access goes up, which are all good things. How do you ensure that we have a ability to do that?

I don't really know the answer. 

Dr. Linda Bluestein: Yeah. And when it comes to variants of uncertain significance, if we were to do a whole genome sequencing on, I don't know how many, pick a number of people, they're all going to have some variants of uncertain significance, right? That's, yeah. Yeah. 

Dr. Paldeep Atwal: We all have unique variants, unique to us, otherwise we wouldn't be unique.

Right. So, uh, the question As for the lab, when they see these, some of them are easy. They're not, they're synonymous and they don't cause protein sequence changes or any non near splice sites. So that's, that's easy for the lab to interpret and safely call as non disease causing. Some, but some of them are challenging.

I think that the way we get around that now we're in a discussion on variant interpretation, right? One has really helped. One thing that's really helped us is having [00:46:00] larger and larger and larger databases. I remember. Uh, when there was, uh, you know, the, the thousand genomes project, right? And then, and then the UK came out with the UK 10 K.

That was kind a catchy phrase they had, right? Mm-Hmm. . So 10,000 genomes. Then there was a hundred thousand genomes project. Now I don't even know how many there are in XA and nomad. We've, we've got huge amounts of data and it's only increasing. Uh, and, and, and more, more than that. We also have a more diverse database.

more, uh, more ethnic back people with more diverse ethnic backgrounds, which has to helps, uh, everyone. And in fact, it helps people with different ethnic background more than it helps people of the same ethnic background, because it tells you what, what's, what's relatable, what's, you know, common, what's uncommon.

And so, um, that all of that put together is helping, long story, is helping our interpretation of genetic variants. Uh, across, uh, all [00:47:00] populations, and you'll see very commonly when you order a test a year or two after, you'll get an addended report from the lab saying, you know, we feel comfortable now that this variant is not disease causing, uh, and we've, we've downgraded it from variant of uncertain significance to benign.

One more point on the variant classification. There's currently five levels of variant classification. That may change in the future, so there's, to reflect the complexities of variant interpretation, so there might even be more levels of, you know, pathogenic, likely pathogenic, BUS, likely benign, benign.

There might be more than that, reflecting a very challenging area of genetics of What does this gene change mean? 

Dr. Linda Bluestein: Mm 

Dr. Paldeep Atwal: hmm. 

Dr. Linda Bluestein: Yeah. And speaking of challenging and gene changes, you probably are going to anticipate this question. The calocrine gene variants that were found by the Norris lab, are you [00:48:00] able to share your thoughts on that?

I 

Dr. Paldeep Atwal: think it's a very, well, first I think the fact that, uh, knowledgeable. Highly intelligent group like the Norris lab are looking at this. It's great. We need more. We need we need five Norris labs, right? And so I think it's that's a fantastic. I I think the the Some of the evidence is is very strong and this has a role I would like to wait until it goes through the formal process of Once you have a research finding you you Put it together, you publish that finding, it goes through a peer review process where it's looked at by other experts in that area, and then it goes through that process and then it's published.

Then confirmed, uh, by, by others as well. I, I think I, I, I, I think I'm tentatively positive . I'll say, say [00:49:00] that I'd like, I'd like to see, you know, we just need to wait until it goes through the, the process. I think. Mm-Hmm. . But I'm 10 tentatively quite positive about it. And I think it's, uh. a major step forward.

Let's, let's just, I'm happy to be hypothetical for a second. If it goes, everything goes through and we can offer testing for that, I think that will be something that will be a positive step in the community. Now, obviously, we're not going to suddenly find the gene change for every single patient with hypermobile ADS just based on one study and one, one finding, right?

There's likely. Uh, many reasons that we haven't been able to find the, the genetic basis of hypermobile ADS. We talked about a few things. We talked about different subgroups within the ADS. We talked about the complexities of genetics, the genotype, variable expression, gene gene interaction. We're not able to test for a lot of those things.

[00:50:00] So, if we're not able to test for it, and if that's the cause, then perhaps we're missing it. Additionally, the genetic sequencing technology we're using mostly is short read technology, which is changing, but there are things that are difficult to capture with that technology, that you require different sequencing technology, long read to see complex rearrangements, triplet repeat disorders, and other, other, um, Deletions of certain sizes can be missed on short read sequencing and not seen on chromosomal level copy number variation.

So a deletion of around 1000 base pairs, it's almost impossible, very difficult, very challenging to detect those things. So there's gaps, so we need to start filling those things in. Maybe it's in one of those gaps that the answer lies. I don't know. 

Dr. Linda Bluestein: And given all of these complexities and the challenges that we face, but also at the same time with these [00:51:00] vast panels that either either panels that we can do or doing, like you said, the price has come down dramatically for doing whole exome or whole genome sequencing.

If someone has red flags for a rarer type of EDS or, you know, red flags for, like you said, vascular fragility or something, then I would think that genetic testing would for sure be indicated in those instances, but kind of as a general rule, what I'm not sure. What do you think are good indicators for genetic testing or good indicators that it's maybe not needed?

In the context of, I guess, somebody presenting with symptomatic joint hypermobility and they suspect that they have hypermobile EDS. 

Dr. Paldeep Atwal: So that's a very relevant question. From my perspective, the threshold is fairly low, given the ease of which, thankfully, the ease of which certainly gene panel testing is available.

So if someone presents with hypermobile ADS, we go through other, um, features and factors [00:52:00] related to Ehlers Danlos Syndrome and other related conditions, Marfan, other things like that. Really, if there's a small, um, Concern at this, at this stage with the ease of genetic testing. I don't, I don't have a, I usually order testing for them.

Dr. Linda Bluestein: Mm-Hmm. , 

Dr. Paldeep Atwal: I, I think the other problem that I've seen in clinical practice is. If someone doesn't have the testing, now let's say they have hypermobile DS but you're very sure it's hypermobile DS and you think, you know, you don't need the testing, I'm very confident you don't have anything else, and that's fine, and this has happened, it's happened to patients, they'll come back later and say, look, this cardiologist I saw or this surgeon I saw, I need this surgery, or whatever it is.

They won't do the testing for me because I wasn't tested for vascular EDS, or something else. And they're not comfortable to do their procedure or surgery or whatever intervention they're thinking of doing [00:53:00] unless that's been ruled out by a genetic test. So, it creates barriers for the patient down the road, unknowingly.

Just from my experience in clinical practice, I'm not saying those barriers are correct, just to be clear, but I'm saying those barriers do exist. So with that experience and that, uh, kinda wherewithal of what will happen to the pa because the patients often see me once or twice and I'll never, uh, may or may not see them again.

I want to make sure in that interaction, I've done everything possible for them. 

Dr. Linda Bluestein: Mm. 

Dr. Paldeep Atwal: So five years down the line, they, they, uh, are, is still useful to them, if that makes sense. Right? 

Dr. Linda Bluestein: Mm-Hmm. or 

Dr. Paldeep Atwal: still, so doing that will, will help in those instances. And, and secondly. There's a big worry and anxiety component people have when it comes to the testing, particularly for subtypes that cause vascular issues and aneurysms.

And clinical reassurance by a medical [00:54:00] geneticist I think is very valuable, but seeing that negative result has a personal utility for the patients in my mind. And that subsequently I think that has a clinical utility. 

Dr. Linda Bluestein: Yeah, and I'm thinking of a, of a Uh, somebody that we also have in common, who you diagnosed with classical like, uh, type 2.

And I know this is so incredibly rare that you might even know who this is offhand. Um, and yeah, this is such, this is the AEBP1, uh, related, right? Type, type 2 classical like, but that person, Hypermobile EDS was what was suspected and I saw them after they had their diagnosis from you. But this is somebody that you did do genetic testing on.

Hypermobile EDS was suspected and it came back that they actually had this like extremely rare type. So that's a great example. That's a great example and a great example 

Dr. Paldeep Atwal: why we do the testing. These are called subtypes. of Ellison for a reason. Subtypes of overlapping similar presenting conditions. Now, as good as we are [00:55:00] clinically, we must know our limitations that sometimes it's really impossible to clinically differentiate.

And so we, we have to rely on, on this, on additional molecular testing, genetic testing, to I'm sure we're doing what's best for the patient. 

Dr. Linda Bluestein: And in that classical like type 2, if I remember correctly, there's different implications in terms of screening for vascular issues, right? So yeah. Vascular 

Dr. Paldeep Atwal: issues, bone density issues, other screening issues as well.

Other medical issues. Other medically relevant things that make it important to differentiate, to your point. 

Dr. Linda Bluestein: Right, right. Yeah. So that's, that's not just like an interesting thing, but that's No, right. It's a 

Dr. Paldeep Atwal: useful, clinically useful, meaningful difference that's going to benefit the patient and their health long 

Dr. Linda Bluestein: term.

Yeah. Yeah. Wow. Definitely. And then you mentioned, uh, briefly about genomics and pharmacogenomic testing. Um, before we wrap up, if you could maybe, uh, tell us, and [00:56:00] I'm sure we could have spent the whole time talking about genetics versus genomics, but if you could maybe, we had a little bit of this conversation four years ago, uh, four years and four months, but if you could just tell us a little bit about where things are at with genomics, uh, what the difference is and, you know, why some people might be considering that, because also that there's direct to consumer testing for that as well, right?

So, yeah. 

Dr. Paldeep Atwal: Well, let me address the genetics, genomics piece and then the pharmacogenetics piece or pharmacogenomics, which I'll address the difference there. So I've heard a lot of people talk about genetics versus genomics, and from my perspective as a geneticist, I don't see a difference. Now, some people will tell you genetics is looking at a single gene.

Genomics is looking at all of genes and the holistic view of many genes interacting together. I didn't realize that was not the case with medical genetics, like, uh, and I think they're really [00:57:00] interchangeable in my mind. And many people may disagree, but I think we're arguing semantics. I don't think it really is true.

For me, I don't think, oh no, I better change what I'm saying. It's not genetics, I need to say genomics. I can't say genomics, say genetics because I'm looking at a single gene. I don't know any geneticist that looks at single genes anymore. So, you know, it might be, the difference may just be reflective of changing times.

When we were only able to look at a gene, it was genetics. Now, genetics meant single gene, but now we're able to look at thousands of genes at the same time. Genetics means thousands of genes at the same time. Genomics. The board, or the American Society, or College, sorry, of Genetics and Genomics, And so I think they're trying to play the field and just call both, you know, I'm a fellow that, I think, you know, I don't, I call myself a medical or clinical geneticist, not, maybe I should say clinical geneticist [00:58:00] and genomicist.

I don't 

Dr. Linda Bluestein: know. That's an excellent, that's an excellent question. Yeah. 

Dr. Paldeep Atwal: So the second thing on pharmacokinetics. I don't even know what to say. Should I say genetics or pharmacogenomics? I think it is pharmacogenomics is the term used, um, is, uh, looking at how your genetics influences your body's metabolism of certain drugs and medications.

Now, most of these are DYP enzymes in the liver that either up regulate or down regulate your metabolism of those conditions. Which Depending on, this is also complicated, depending on whether it's a prodrug, uh, uh, uh, given as a prodrug or active form that that can cause higher or lower levels, right?

Mm-Hmm. , right? And so, uh, it's, it's used in a variety of different areas of medicine, uh, psychiatry. But believe it or not, is the [00:59:00] pro probably the most commonly used area, which kind of is unusual, right? You don't think genetics and psychiatry, uh mm-hmm. As, as being the kind of the, the, the forefront of a certain area of, of genetic testing.

But it is, and in other areas as well, obviously even in anesthesiology, of course, as you know, with the risk of malignant hyperthermia, there's a couple of genes, R1 for example, that is on all of these panels. So the labs are now giving these variants, or these interpretations out. To, one, I think, provide a more complete coverage of testing.

It's not just, not simply clinical variants, it's also pharmacogenetic variants. One of the issues is finding someone to interpret that. What we do, certainly, is we have a pharmacist who's trained in pharmacogenomics and sits with the patient, makes a medication action plan based on that, and doesn't just [01:00:00] look at the genetics, because genetics is not an isolation, or genomics is not an isolation, it's a It's also other drugs they're on, drug drug interactions, so there's, you think of these, you could think of these as gene drug interactions, but then there's drug drug interactions, there's phenoconversion, having, being on drug A can actually influence how well or, or slow drug B is being metabolized.

So that, that's all relevant in a, in the soup, as you referred to earlier, right? It all plays a role together, you can't, you can't take them in isolation, so that's why looking at all of them together is the right thing, the right way to look at it. 

Dr. Linda Bluestein: Yeah, that's, that's, uh, really fascinating. And I know that yes, in psychiatry, this was something that was definitely done many, many years ago and, and definitely it seems like it's becoming more common.

Do we have the same problem with, uh, not just difficulty in interpreting the information, but possible inaccurate results if people are doing the direct to consumer level of lab [01:01:00] versus the clinical lab? 

Dr. Paldeep Atwal: I think the inaccuracy will exist in all aspects of testing if the right processes aren't followed.

I always look for labs to have CLIA and CAHPS certification, uh, through all aspects of their testing, not simply the sequencing part, well, they're not going to give it if it's just one part, but the, these kind of validation recognition from regulators. And testing. So these regulators will regularly submit a sample to the lab and ask them what's in the sample to ensure that they're able to detect the right things.

So they're always being challenged and being made sure to show that they're able to detect the right variants when they are there or not there. So I think the short answer is yes, the risk remains even in pharmacogenetic testing. Most pharmacogenetic [01:02:00] testing looks at, uh, certain polymorphisms of the gene, so the testing is often a little bit simpler, but that being said, now there are groups looking at doing full sequencing of those genes to look for other variants that are not even on those panels.

that could be missed. So if you have a test that only looks for presence of a variant and you don't find that variant, that doesn't mean there's not something else that you didn't look for that's also relevant in terms of drug metabolism. And there's 

Dr. Linda Bluestein: other things besides drug metabolism, right? That we can look at for genomics.

Yeah. 

Dr. Paldeep Atwal: Yeah. Yes. Oh, absolutely. There's, now there's a complex trait. So polygenic risk scores. And for cardiovascular disease, diabetes risk. Cholesterol, other, all sorts of conditions, neurodegenerative conditions as well. These are still [01:03:00] nascent in many ways, it's, I think that there, we'll see a lot more of that in the next three to five years.

Maybe on our next blog we can talk more 

Dr. Linda Bluestein: about that. I can't wait to see what that conversation is going to be like. Okay, so I like to wrap up every episode with a hypermobility hack. What hack do you have for us? So like some quick tip or quick win for people. 

Dr. Paldeep Atwal: So this, this has to be a physical thing. It could be anything.

Dr. Linda Bluestein: It could be anything. So, so basically, uh, you've, you've given us already quite a few, like looking for a CLIA certified lab for, for example, and looking for labs that maybe you have the ability to, it's not just direct to consumer testing, but the direct, um, access for, for ordering. So, uh, something that people can do that they could, a tip that they can take away right away.

Dr. Paldeep Atwal: I think one tip that I, I, Brian, [01:04:00] well, let me give a couple, so, uh, so the first, very simple avoid things that make your joints worse, impact exercises and maximal stretching. So they go to the limits of their, if they do, if they like to stretch and many people like to stretch, it makes them feel better, try and limit it to around 80 percent of what they can do.

And then the other one, I think maybe the most important. is work, at least for a small time, dedicate some time to working with a knowledgeable physical therapist trained in Ehlers Danlos Syndrome. Ideally, that's someone that, usually they have the condition, if they have Ehlers Danlos themselves, that's a great sign.

So, someone that really knows about it, and can work with them and look at how they're doing certain movements, work to reprogram certain things. And certain muscles are activating, how they're doing certain joints, certain movements, it's amazing how inefficient some people are moving, hence they're more tired, hence they've [01:05:00] got more pain, just reprogramming how they're doing simple movements they're doing dozens and dozens of times a day.

It makes a huge difference. 

Dr. Linda Bluestein: That makes a lot of sense. Okay. So before we really, really wrap up, um, I, I first of all, I just want to thank you so much for coming on the Bendy Bodies podcast again and sharing your vast wisdom and knowledge with us. This is such an important topic and I feel like it's so much more nuanced than most people realize.

So, so thank you so very much. 

Dr. Paldeep Atwal: Thanks. Always a pleasure. And like you said, let's plan maybe a maximum of two years, if not one year next 

Dr. Linda Bluestein: time. 

Dr. Paldeep Atwal: Yeah, 

Dr. Linda Bluestein: definitely. And before you go, can you let us know, first of all, where to find you and also if you have any special projects, research that you're doing that we should be aware of?

Dr. Paldeep Atwal: Yeah, so I'm based in West Palm Beach, Florida. I do also, in terms of clinical practice, I see patients in the office in downtown [01:06:00] West Palm Beach and also online as well. Many patients choose due to travel reasons and difficulty, they can't travel so they see me online. So I'm doing some, have a couple of cases that We're publishing on unusual presentations and types of those.

I'm on some new genetic findings for not new genes but new, new variants in those genes that I've got some students working on. And I'm also, I'm also doing more education. I'm planning on Well, maybe I can recruit you right now. I'm planning on a, uh, one day kind of conference for patients. Patient focus where I bring in, I'll talk, I'll bring in some experts.

And we really talk about different aspects of LSDAM loss. I think that, like you said, there's many patients that just don't have access to genetics, don't have access to people like you and I, and it's [01:07:00] something that they can watch from their house and they can, similar to the education you're doing here, they can really take away from experts in the area, things that may be of use to them, or at least help them.

advocate for themselves as well. So I'm hoping to do that within the next year or so. 

Dr. Linda Bluestein: That sounds fantastic. And I would, I would love to be involved. I think that's a wonderful idea. Like a, like a boot camp. 

Dr. Paldeep Atwal: One day, just a one day thing. Yeah. 

Dr. Linda Bluestein: Yeah. Yeah. I think so many people could benefit from that. And I think that, you know, these conditions require people from so many different disciplines.

Or, or I should say maybe don't, maybe would benefit from people with different backgrounds. So I, I love that idea. I think that's really. Really great. Yeah, cardiologist, 

Dr. Paldeep Atwal: GM, motility specialist, physical therapy, of course, physiatry, so medically trained doctors who specialize in physical medicine, pain management, of course.

It's [01:08:00] huge. So many, you know, neurosurgery, all of these, all of these Actually, you know, I'm going to have to, that's too many already. 

Dr. Linda Bluestein: I was just going to say, this is sounding more like, but that, but that's okay. I mean, I think, uh, everything's an evolution, right? So you and I have been communicating for a number of years, even before we had our conversation, you know, four and a half, four and a half or so years ago.

And your practice has evolved. My practice has evolved. We're constantly trying to meet the needs of our patients. as best we can and be able to offer them the kind of support that we want them to have. 

Dr. Paldeep Atwal: Absolutely. Yes, that's the goal. 

Dr. Linda Bluestein: Well, well, thank you so much again. It was so great to see you finally, and I look forward to our next conversation.

Dr. Paldeep Atwal: Likewise. It was really a pleasure. Thank you, Linda. 

Dr. Linda Bluestein: Yes, absolutely. Oh my gosh, that was such a great conversation with Dr. Atwal, and I'm so grateful to him for coming on the podcast a second [01:09:00] time. We will definitely have him back much sooner than four years and four months from now and get a follow up conversation about genetics because, as I'm sure you are now very well aware, it's so much more complicated and so much more nuanced than most of us are aware.

I know I learned a lot from this conversation, so I hope you did as well. And thank you so much for listening to this week's episode of the Bendy Bodies with the Hypermobility MD podcast. You can help us spread the word about joint hypermobility and related disorders by leaving a review and sharing the podcast.

This helps raise awareness about these very complex conditions. If you would like to meet with me one on one, check out the available options on the services page of my website, hypermobilitymd. com. You can also find me, Dr. Linda Blustein, on Instagram, Facebook, TikTok, Twitter, or LinkedIn at hypermobilitymd.

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