With the establishment of the Joint Cardiovascular Genetics Clinic, medical genetics is now an integrated part of pediatric cardiology at UCSF. In this talk, Christina Theodoris, MD, PhD, and Rachel Farrell, MS, CGC, describe what this clinic offers: the many types of tests available, what they do (and don’t) reveal, the value of carrier testing for family planning, and how experts determine which tests are appropriate. Case studies illustrate how knowledge of certain variants can protect a child’s future health, lead to lifesaving care for family members through cascade screening, and open the door to new treatment opportunities. Learn which patients to refer and how the process works.
All right. Hopefully you can see the slides. So we're excited to speak with you all today on the topic of cardiovasculargenetics, practical clinical applications for pediatric patients. Rachel, I'll start with telling us about the agenda and some of the departmental overviews. Thanks, Christina. Um, so wanted to just review some of the agenda items that we'll be reviewing today. Um, we wanted to just give a brief overview of how our genetics and cardiology divisions are connected and are intertwined. Next, we'll discuss the benefits and types of uh genetic testing that we offer to our patients. We have two case studies that we believe are exemplary of the types of patients that we see in our cardiovascular genetics clinic. And then we'll end by discussing logistics on how to refer patients to our clinic. Next, So, with, with that said, you will are really the front line as primary care, um, physicians and pediatricians. You're really the ones to, um, see our patients the most frequently. And if a patient presents with any cardiovascular symptoms like chest pain, um, or shortness of breath, you're really the ones to assess and triage appropriately. Um, our pediatric cardiology division is known as the Pediatric Heart Center, and although we offer general cardiology services, we also have a variety of specialty clinics, including a cardiomyopathy clinic, an electrophysiology and arrhythmia clinic. We also have an aerotopathy clinic which uh caters to patients with aortic valve disease. We also tend to see a lot of patients with connective tissue conditions in this clinic, and we also have a heart failure clinic. Uh, next, for approximately the last 7 years, we've been working to build a genetics presence within the pediatric Heart Center. Um, and this is in the form of offering, uh, genetic counseling via telehealth or video visits to our patients with either a personal or family history of inherited cardiovascular disease. And most recently, Doctor Theodoros and I have worked to collaborate to create a joint cardiovascular genetics clinic. And the idea is to leverage Doctor Theodoros and her expertise in cardiovascular genetics and further integrate genetics within the pediatric Heart Center. We've historically had to um For patients out of the heart center if they needed genetic services. And now this offering of this, of our joint clinic allows for um further integration um within uh the cardiology space. We can collaborate with our cardiology uh colleagues and also streamline both genetics and cardiology services for our patients. Um, I'll turn it over to Doctor Theodoros, who'll talk more about the benefits and types of genetic tests that we offer to our patients. Thank you, Rachel. So, yes, I think the primary benefit of genetic testing is so that we can inform medical management, and there's different ways that this can happen. So first, uh, it would be through medications that could be found to be more effective depending on the underlying genetic cause of disease. So for example, if you know that a cardiomyopathy is due to rasopathy such as Noonan's syndrome, then you might consider treatment with meth inhibitors, which are a targeted treatment for this pathway disruption. Additionally, this can be uh informative for initial screening as well as continued surveillance for associated manifestations. So, for example, if you know that a neuropathy patient has Marfan as the cause of that, then you know that you need to also Pursue ophthalmology screening for some of the eye changes that can happen with this disease. And so it allows us to be able to uh target the other associated manifestations in other organ systems, both with initial screening and surveillance for progressive conditions. And finally, it allows access to ongoing clinical trials and newly approved treatments. Um, so for example, if you know that a cardioopathy is due to Dana disease, you can more quickly be able to get that patient um access to some of the ongoing clinical trials or, you know, when the treatment uh is eventually approved, to be able to be immediately starting on that treatment because you know that the genetic condition lends itself to that targeted treatment. Additionally, uh, knowing the genetic diagnosis can be helpful for recurrence risk for family planning. This is both for the parents who might be planning to have additional children, as well as eventually for the patient. Of course, we work with uh mostly pediatric patients, um. But it can also be important to know that genetic testing may be more easily covered for patients less than 18 year olds. So this might, the information might be important for them to have so that eventually when they're planning a family, um, they already have the genetic cause of their disease. And the options of ways to use this information include, for example, in future fertilization with pre-implantation genetic diagnosis, which is usually pursued for a very severe life-threatening genetic conditions um where you can screen embryos with IVF to be able to uh implant those that do not have the inheritance of the disease based on the genetic diagnosis. Additionally, it can be really important for being able to have the team prepared to help manage the patient once they're born, if you're aware of this prenatally, so NICU can be prepared to accept a patient and provide that initial life-saving treatment that might be needed upon the patient's birth. Additionally, it's important for cascade testing for at-risk relatives, so this can really be a life-saving for relatives that wouldn't normally be screened for a condition like aortic aneurysm, let's say, um, but if we know that Uh, their relative has this condition due to genetic change, and we find that they also carry this genetic mutation, then we can perform the screening so that we can catch, uh, some of these conditions prior to rupture, let's say for aortic aneurysm, which of course has a high mortality rate. Additionally, it can prevent unnecessary lifetime screening for at-risk relatives who are negative for genetic variant. So if we know that the aortic aneurysm running in the family is due to a particular genetic change, and we don't see that in a sibling, let's say, then we don't need to continue. Screening that patient, um, which we otherwise would need to do if uh there's a progressive condition that, you know, might not be present initial testing, but we might need to continue monitoring for. Um, so it can also prevent that unnecessary, uh, lifetime follow-up for patients. The risk of genetic testing, uh, primarily center around uncertain results. So for example, you might have a result that's a variant of uncertain significance, which means such a genetic mutation that we haven't seen enough healthy or diseased patients to know for sure if it could cause a disease. Um, because we all have many mutations that, you know, just make us unique individuals but don't necessarily cause disease. So even if we know that a gene is associated with disease, we might not know that this particular spelling change in the gene, uh, the gene would cause any problem or not. And these are often reclassified over time as we continue getting more information uh from noticing that the mutation is occurring and healthy people, therefore reclassifying it as benign or seeing the mutation uh repeatedly in disease patients and therefore pushing the classification to pathogenic. A negative result can also, uh, in some way be uncertain, um, because in some ways, yes, we've ruled out certain conditions, uh, in known mutations, but it doesn't necessarily rule out a genetic cause because we don't know all the gene changes that can lead to a disease. Um, and also, you know, you might have started with, uh, more neuro tests and then if you need to pursue a broader test that can help to uh fill in some of the other potential genetic causes that weren't covered by the more narrow test, um, and specifically, uh, for some of these genetic testings, uh, cases that are very broad like exome or genome, we're sequencing all the protein coding parts of the genes or all the genome in general. These can also be reanalyzed for free at a later date, and we usually wait about 2 years that there's enough new information in the literature, but that allows us to look back at the same data and help to uh reclassify or identify new variants that might not. Have been known to be related disease at the time, but now there are additional research we've identified or associated. And so a negative result, uh, can be, you know, have some uncertainty, but it also has the opportunity to, of continuing to reanalyze in the future to identify potential causes. Um, the other potential risk of genetic, uh, testing when we're doing parental testing for inheritance is that we might, uh, lead to an unexpected diagnosis of a parent. Um, it could also reveal non-paternity, and then additionally, uh, you know, when we're doing genetic testing for a patient that has a diagnosis, it's not really going to affect, uh, you know, their health or life insurance, let's say, because they already have the diagnosis. But if it's a healthy parent that we don't actually, um, you know, have any prior diagnosis. then a new genetic risk information can affect things like life insurance that are state by state or can cause them to be ineligible for certain, for example, high exertion jobs that might exclude an applicant with arrhythmia risk um because of uh the safety of the job. So, although health insurance is federally protected from discrimination using genetic data, some of these other things like life insurance or um specific job opportunities might not be protected. So that's another potential risk for when you're testing a healthy patient for inheritance. Um, additionally, in terms of selecting the type of genetic testing, there's, uh, some considerations that we take in terms of what is the appropriate genetic test. So I'll just review a couple of these here just so you know the types of things that we're thinking about when a patient comes to our clinic. So, uh, a narrow test, um, of course, can reduce the uncertainty if it's very narrow. Uh, so if you have a clinical diagnosis that's very high confidence, then that would be a case where you can pursue a narrow test, for example, testing a single gene if we're very confident that this is a gene that's associated. Or for example, if it's a known familial variant and you're just testing to see whether this patient inherited the variant or not. However, um, of course, if you don't have a very high confidence clinical diagnosis, then usually it's recommended to take a bit of a broader approach because it can actually yield faster diagnosis and overall save costs that would otherwise be incurred by retesting multiple single genes or multiple panels, um, if the first one is negative and there's, you know, a low chance of having picked the right gene, uh if you don't have a very uh strong clinical diagnosis. Broader tests do have more potential for uncertain diagnosis because you're testing more things, um, and there's some parts of these really broad tests that are not really fully interpretable at our current knowledge. So for example, for the genome where you're testing not just the parts of the genes. That code for proteins, but all the intervening gene sequence that's really important for regulating the activity level of those genes. We don't really fully understand the regulatory grammar at this point. So at the clinical level, a lot of these regulatory regions are not analyzed or, or could yield more uncertainty. However, as we talked about, there's always the opportunity for free reanalysis as we learn more over time. And finally, the other uh kind of specific thing to think about, um, to know about is for carrier testing. Um, which, uh, might happen with uh a patient that's planning a family or who's already pregnant. These patients, um, might pursue carrier testing. And the important thing to know is that there's a bit of a distinction with carer testing and that here we're testing healthy individuals to see whether they carry a genetic change that could be passed on to um a new pregnancy. And so in that case, Um, we're only really testing for genes that you need two copies to be changed to cause the disease, so it has to be inherited from both the mother and the father. And the reason for that is, uh, to essentially avoid an unexpected diagnosis of a parent. And so a lot of times these tests, if there's an uncertain change that they might see, if it's not a case where, um, you know, you know for sure that this genetic change can lead to, uh, The disease, then those are not reported. It's like there's a higher threshold for confidence in reporting these variants, and generally they're focusing on autosomal recessive conditions where that single copy in a parent would not cause disease to not have this um unexpected diagnosis. And the additional part of genetic testing um that you might, uh, you know, notice patients uh would opt into in some cases is called secondary findings. And so in this case it's from these very broad tests like exome sequencing where we look at all of the genes and the genome. Um, you have the opportunity, uh, to opt in to secondary findings, which refers to a list of genes that has been identified, um, that are medically actionable. So these are not related to the primary diagnosis of the patient, but they're genes like, for example, cancer predisposition syndrome genes or arrhythmia genes where we would have a clear me. plan of action to help to prevent a negative outcome associated with them. For example, earlier cancer screening or ICD placement for arrhythmias. Um, and so these, uh, are secondary findings that patients can opt into with some of these broad tests that are not related to their diagnosis but could uh give preventative information for them. So in terms of types of genetic testing, um, there's an array of genetic tests that we have in our toolbox that we consider depending on the type of uh diagnosis that we're looking at, um, or we're trying to identify. And there's, uh, both benefits and limitations of each of these. And so, of course, it's not something that um You know, you necessarily need to know a lot of, uh, detail about, but I think it's useful to just have a general overview of these different types of tests because sometimes the patient might have done some of these more narrow tests previously, um, but it doesn't mean that they've really fully exhausted the test. Genetically and specifically a lot of times when there's a new uh birth in the hospital, a patient might get some initial tests like a care type, let's say, um while they're in the hospital, but then the expectation is that they would go home and perhaps follow up with genetics for a broader test. Um, to be able to better understand the genetic diagnosis. And so sometimes these patients might get lost to follow up, so it's important for, you know, be able to help bring them in, especially as they're following up with primary care if there's cases where um they might have had some of these, uh, more narrow tests, but there's potential for uh important genetic diagnosis information with a broader test. Um, and so. Here I've kind of structured this table to give an overview of the types of different variants that these different genetic tests are really going to be as saying versus they're not going to be able to capture them. So some genetic variants are copy number changes, so an increase or a decrease in the number of copies of a gene, uh, balanced structural changes, so all the DNA is there, but there's a piece that's moved to a different location, and so it's balanced, there's nothing extra missing, but it's moved to a different place and that structural change can disrupt genes that are at the border of where that break happened. Uh, regions of homozygosity refers to areas where normally we would have, you know, two chromosomes that lead to some diversity in terms of, uh, the sequence of the gene on one chromosome and the gene on the other chromosome, but in some cases, you might have large Regions where the sequence is exactly the same and that can happen either, for example, with consanguinity of parents or um with cases where one chromosome is lost um during uh a new pregnancy and, and replaced by a copy of the, of the same one. And so in these cases, these uh regions of homozygote are important because there's more likely to have a recessive uh uh recessive diseases occurring here because if there's a mutation that is on one and then it's copied on the other, then it's gonna happen on both of, of the alleles and lead to that disease compared to other diseases where, um, you know, other cases where you have more diversity, it's unlikely for the gene to have the mutation on both of the alleles. And then point mutations are more like spelling changes, so that's really more high resolution tasks are needed to find, to find those fine spelling changes as opposed to large pieces gained or lost. And repeat expansions are things where you have repeats in the genome and then you might have an expansion of those repeats that can disrupt um the the region or the protein that's made. So things like Huntington's, for example, you might be familiar with that are related to this. And so all of these are related to the genetic sequence itself, but it's important to know that methylation can also cause disease, and methylation is something that's not actually the gene itself, the DNA itself, but it's a modification on top of the DNA. And that's an epigenetic change. So things like Prater Willy or angelman syndrome are associated with methylation changes. So any genetic tests that are looking at the DNA itself would completely miss a change in methylation that can lead to these disorders. Um, so we'll talk about kind of which of these different tests to be looking at. Um, and then here in this last column, I just have a kind of indicator for how narrow or broad the test might be. So just to briefly go over some of these um for karyotype. In this case, we're looking at all of the chromosomes, so in that sense it's broad, but it's a really bird's eye view. So we're just looking at, generally, OK, here we can see there's 3 chromosome 21s that leads to Down syndrome, um, but we Only see some major changes like that. So large copy number changes or a balanced structural change. So, you know, an entire chunk of chromosome 3 has moved now to be attached to chromosome 4, let's say. Um, so then all the genetic, uh, information is still there, but that break point might have caused an issue at the gene there. For uh fish, this is something that is also related to copy number changes and the main reason we do this is because it's very fast, but it's also a very narrow test. You have to have a very specific thing you're looking for. You might say this done with patients that have 20. 2Q11 uh syndrome because that's that's caused by a deletion on chromosome 22 and this is a test that can be done within 1 to 2 days, so can lead to a very quick uh diagnosis, you know, when the baby is first born in the hospital, for example. Um, and so here this test, normally you have a, let's say a green that's a control where you see there's two copies of these other uh chromosomal locations, but then the red, you see this is a normal case where you have two copies, but here you only see one and so that means there's a deletion in the other one. And so this red is specifically looking at 22Q11 region. So this one really only looks at these copy number changes and it's a very narrow tests. Microarrays such as you might see commonly done, where again it's broad and it looks at the whole uh genome, but it only looks for these copy number changes and it can seem more fine copy number changes compared to a krotype where it's A bird's eye view. Here you're looking at more specific points within the genome and you can see black means that there's about 2 copies of everything, but this particular region, there's less copies, so this is a deletion of this region. Um, so here you can see, you know, a smaller fine mapping as, as you can see here by the number of base pairs, a smaller fine mapping of a deletion, um, but, uh, you cannot see to the level of a spelling change. So with single gene tests, here you can see the level of a spelling change, and these are sequencing tests. Um, so in this case, you can look for a particular gene if you have a very high level, uh, high confidence clinical diagnosis and you can see if there's specific spelling changes in that gene. So it's able to capture these point mutations as opposed to these other tests we talked about before. However, you're really only looking at this one gene. Whereas with the genetic panel, you can perform that test for many different genes and so it gives you a little bit of a higher yield when you don't have a very high confidence single gene diagnosis. And then with the exome test, it's even broader, but again a sequencing-based test. So here for a panel, you might sequence gene one if it's in the panel but not gene two, whereas with the exome, it's sequencing all of the protein coding parts of the genes. So all the parts of the genes that lead to proteins. Um, and so that's a much broader task because you're looking across the whole genome, but only these protein coding regions. And finally, with the gene test, you're looking not just at the protein coding, but also all these intervening regions that are important for regulating the activity levels of these genes. And so here you have the broadest level sequencing test where you can see all of the um genome or check all the genome for spelling changes. And you can also find things like copy number changes or repeat expansions from this type of test. And uh this can be done to sequence both the nuclear genome as well as the mitochondrial genome, which is important for a lot of uh mitochondrial diseases as well. Now, in addition to these broad sequencing tests, you can, if you're looking specifically for repeats, like for Huntington, let's say, you can do a type of test that only looks at those repeats. But all of these that are looking at the DNA as you mentioned before, do not cover any methylation disorders. So cases where angelman or Prater really is due to methylation change, you really have to do a methylation test. And so there you're looking for something specific, but uh it would not otherwise be covered. So it's important to know that um without having done this, you can't really rule out those conditions. And finally, all of these are looking at some kind of uh genetic change or methylation change, but in some cases, we don't know what's causing the disorder, but we can still assay the metabolites to identify a metabolic disorder. So even if you don't have a known uh genetic diagnosis, you can identify a metabolic disorder that could potentially be treatable based on a change in the metabolites. So you can always do uh metabolic testing for that reason. So this kind of covers an overview of some of these genetic tests that we have in our toolbox, and again, uh, something that we just wanted people to be aware of that it's not like we only do one thing like exome testing, but there's many different types of tests and there's different types of uh variants that we're detecting by them. And so if a patient comes and says, I've done genetic testing, it's negative, but they've only done some of these narrow tests, um, there could be additional uh value to having them re-refered. So now we'll move on to some case studies, and Rachel we'll start with the first one. Thank you, Christina. So this first case study is that of a 12 year old female. Um, she was actually initially ascertained after um her annual exam with her pediatrician who noted a heart murmur on exam. Um, the pediatrician assessed that there's no family history, but given the heart murmur, wanted to refer the patient um to cardiology. So her um cardiology evaluation included a physical exam um and she had several physical findings that were noted including pectus excavatum. She also had flat feet, arachnodactylate, and she was 83rd percentile for height. Um, her cardiac exam was also significant. She was noted to have mitral valve prolapse, and she had, um, significant aortic root dilation, um, corresponding to 3.3 centimeters, um, with a Z score of 4.2. Uh, Z score of over 2, is abnormal, so the patient was definitely over that threshold. Uh, at that point, um, the patient, uh, was, uh, started on losartan to mitigate her aortic dilation and was referred for genetic testing given both her physical, um, and her physical findings as well as the findings on echo. Um, at that point, the patient saw me for genetic counseling. Um, we ran an aytopathy panel which consisted of 35 different genes. Um, and the patient was found to carry a pathogenic loss of function variant in a gene called fibrin 1, also known as FBN1. Um, this specific mutation causes a premature stop codon and protein truncation. Um, and it's associated with Marfan syndrome. Um, the variant or mutation itself was, was novel and rare, but given the mechanism of disease, we knew that this variant was pathogenic. Um, her physical findings also supported the diagnosis. Um, and many times we find these variants, but there's no, um, reported cases in the literature, um, at the time that we, uh, give the patient the diagnosis. And in these settings, when we identify mutation in a pediatric patient, we want to determine inheritance. Um, Marfan syndrome, for example, has a 25% uh de novo or spontaneous rate, and given that this patient had a sibling, um, and obviously there were relatives on both maternal and paternal sides, we want to determine um if this was coming from a parent or not, um, and mom was found to carry the variant. Uh, this is an interesting case because just looking at mom, she didn't have any overt features of Morphine syndrome. She was moderately tall, about 5'7, 5'8. She had some joint hyperflexibility. Um, she never had a reason to get an echo or cardiac exam and didn't, um, report any symptoms, and she did not report any ocular symptoms either, no lens dislocation, but she did have mild myopia. And interestingly, um, mom herself was very, uh, very motivated, very savvy. She was also dealing with a lot. Her 12 year old daughter had just been diagnosed with Marfan syndrome. She received the diagnosis several months later, um, and she was very motivated to get an echo herself, which was very fortuitous. Her echo at that point showed severe aortic root dilation. Um, corresponding to measurement of 5.1 centimeters. And we typically recommend surgical intervention, um, at 5 centimeters or greater. And she's now, um, in consultation with cardiothoracic surgery. She's gonna be started on treatment. Um, and this is uh just a good example of the importance of genetic testing and then cascade testing for family members. Next. Marfan syndrome is an autosomal dominant disorder. Um, it impacts the fibrous connective tissue. And, uh, I think one of the most important features of Marfan syndrome is that it's highly clinically variable even within family members. Um, I think this family is a good example of, um, how really we wouldn't have known this diagnosis if it wasn't for an astute pediatrician that referred her for the murmur. Um, if mom and dad were not available for testing, we wouldn't have known the inheritance and been able to cascade it out in the family. Um, Morphine syndrome is, uh, encompasses three different, um, systems. So typically, patients with Marfan syndrome have involvement of the skeletal, ocular, and cardiovascular systems. And it's a relatively common connective tissue condition compared to others. There's a 1 in 5000 prevalence and aortic dilation is found in about 60 to 80% of all patients with Marfan syndrome. And I think for pediatric patients, it's usually the kind of key presenting features that tips us off to Marfan syndrome in conjunction with some systemic features. And it accounts for 3 to 5% of all aortic dissections, and I think um You know, it's, it's so important to identify patients with this predisposition given the, um, given how lethal aortic dissections can be for patients. Now, we know that the uh molecular testing for Marfan syndrome is quite good. The diagnostic yield is quite high. However, uh, genetic testing will not identify all mutations in FBN one. And so there is uh clinical criteria that we have. So I just wanted to show you all this slide. It's also known as the Ghent diagnostic criteria. So you can see there's combinations of um different features that can lead to a clinical diagnosis of Marfan syndrome in the absence or the presence of family history. And on the next slide, um, there are a host of different, um, features, uh, physical features that can um Uh, provide a systemic score for us when we're assessing for Marfan syndrome. So there's a maximum score of 20. And for patients that have a systemic score of 7 or greater, plus aortic root dilation with a Z score of greater and the absence of the family history, for example, that's clinically diagnostic for Marfan syndrome. Um, and so these are the things that, um, cardiologists can assess for and certainly, um Doctor Theodoros and I can assess for in a genetics visit. And if you look down, you can see too that there are certain facial features that are associated with Marfan syndrome. Um, and I wanted to just end my case study with some photos of patients that we pulled from uh a website um called Positive Exposure. Um, and just wanted to highlight again the clinical variability of this condition that um we thought these were good examples of patients that, you know, may come through your clinic. Um, so have some, um some photos. So these Patients again are all patients with Marfan syndrome. And again, can come through your clinic. So, I will turn it over to uh Doctor Theodors who will review um our second case. Thank you, Rachel. So in the second case, we had a pair of siblings. So the first was a 17-year-old girl who was uh sent to us from cardiology after being diagnosed with hypertrophic cardiomyopathy and also had some other manifestations including muscle pain, uh pigmentary change, a blind spot on the optic disc, androgenic androgenic alopecia, um, cebric scalp dermatitis, and elevated BMI. And then her sibling, her brother was a 15 year old boy. He also had a borderline septal hypertrophy and elevated left ventricular mass, and as well as ventricular ectopy, but additionally he had myotonic dystrophy, so perhaps more severe than the muscle pain of his sister, severe global developmental delay, and subclinical hypothyroidism. So there were some shared features, uh, whereas and uh some of the features were more severe and the, the, uh, brother. We also learned that there's a family history and the mother of also having ventricular hypertrophy, where she initially presented with palpitation as a tachycardia when she was 33, and then was found to have this concentric left ventricular hypertrophy and atrial fibrillation of rapid ventricular response, and she was at that point status for multiple ablations with recurrence and transvenous ICD placement. So when we performed genetic testing for the siblings, we found them were both positive for a pathogenic lamp 2 variant. Um, which is an intronic variant, so between the exons that code for the protein coding parts at a spice site. So it, although it doesn't affect the genetic spelling of the gene itself, it's affecting the splicing of the gene, and it's associated with X-link dna disease. It's rare but a well-described variant, and it's been noted in multiple publications, and so it was classified as pathogenic. And then we found the mother was also positive for this lamb 2 variant, and lamb 2 is involved in the lysosome, which is important for uh degrading a lot of the, uh, you know, protein fragments, etc. that are within the cell, and important for the autophagy of those cells, and without proper lamp to function, there can be buildup of these uh uh components that are not properly degraded and can lead to dysfunctions in these cell types. And uh it's important to note that although it's an excelling disease, which we often think of as only impacting males, it's also uh common to have and disease manifestations in females, albeit to a lesser degree of penetrance. So females, for example, can also have hypertrophic cardiopathy, but it's a 96% penetrance in males, whereas only 30 to 70% females. They can also have cardiac conduction abnormalities, uh, skeletal muscle weakness. Um, the intellectual disability is much more common in males, uh, whereas the retinopathy is pretty much equal between males and females. And so for us, it was really important to have been able to make this diagnosis and the patient to know what was the cause of the cardiomyopathy, um, because there was actually a phase two clinical trial that was available for gene therapy for Dana disease. And so our 15. year old boy patient was enrolled within this clinical trial, um, and this is a gene therapy that, uh, introduces a trans gene for lamp 2, and specifically being performed in male patients, uh, with DNA disease. And so this is really important that he was able to get early access onto this clinical trial, um, and also, you know, he's really uh part of paving the way for this uh gene therapy uh to that could potentially uh be effective for um many other patients and initial results from that phase one look very promising. So those are two key studies that really highlight um the benefits of genetic testing that we talked about. Uh, so now I'll turn it over to Rachel to talk about how to refer patients. Thanks, Christina. So there's two ways that you can refer patients to our joint cardiovascular clinic. Um, you can place a referral via EPIC, and it's a general referral to pediatric cardiology, so the way that you would for general cardiology or an echo and EKG, um, important thing, um, is to specify that this is for the joint clinic and to CC myself or Christina, um, whether that's routing the referral or sending us a message. We wanna, um, attend to these referrals in a very timely manner. So please let us know if you are placing a referral. Um, you can also call the access center, um, and place a referral that way. Um, we offer a clinic once a month, um, for new patients, and we do require that they come in person. That's to really leverage the importance of the physical exam, meet the families, have a discussion in person, um, and that's That's the first Wednesday afternoon of the month. Um, we do not require that patients come in for follow-up visits, um, in person. We offer virtual or telehealth visits for that, um, to review any genetic test results or anything else that, um, wasn't covered in that initial visit. That's the 3rd Wednesday afternoon of the month, um, for patients that need um follow-up. And we wanted to just um give an overview of the types of referral indications that are appropriate for our joint clinic. Um, so we see pediatric patients, of course, whose primary medical condition is cardiovascular in nature that have one of the following three features. One, either dysmorphic features and our manifestations in other organ systems outside of the heart. Uh, the patient can also have isolated structural heart disease or um another type of isolated cardiac um disease. Uh, where the patient has had prior negative panel testing. So, for example, maybe they've seen me for genetic testing, the patient has a suspicious family history, a striking phenotype, um, and had negative or uninformative testing. Um, I'll discuss the, the case with Dr. Theodores. And many times we think it would be beneficial to offer broader, more advanced testing, um, to help, uh, to help us see if there's another genetic etiology that wasn't captured on prior testing. And with that, I will hand it over to Doctor Theodos who will review just some of the main points from our talk. Yeah, so hopefully that was informative in terms of how we think about these patients when they come to our clinic and some of the types of cases that we see. Uh, again, really the most important aspect is for genetic diagnosis, it, it will allow informed medical management and screening of that risk individuals which uh can really be, uh, life saving for a lot of the patients that we see. Additionally, um, the joint cardiovascular Genetics clinic is integrated within the pediatric heart center, uh, to provide genetics care to cardiovascular patients, um, in this, uh, integrated manner. And then finally, um, you're able to refer through Epic for patients with a primary diagnosis of cardiovascular disease who would benefit from genetic evaluation.
