Focused on the needs of the entire family, the genetics program for young patients with heart disease at UCSF Benioff Children's Hospitals offers complete care from experienced specialists. Pediatric electrophysiologist Karyn Austin, MD, PhD, and genetic counselor Rachel Farrell, MS, CGC, describe available services, including highly specific DNA variant evaluations and personalized education that can be lifesaving. A case example shows how inheritance information and advanced diagnostic studies can help patients and family members take control of their heart health.
Hello, today I'll be speaking about our comprehensive pediatric cardiovascular genetics program. My name is Rachel Ferrell and I'm a genetic counselor. I help to coordinate all of the genetic evaluations in our pediatric heart center for indications related to inherited cardiovascular disease. Our comprehensive pediatric cardiovascular genetics program consists of three independent but overlapping programs. The first being our inherited cardiac arrhythmias program that's led by Doctor Karen Austin. We also have an aortopathy program that's run by Doctor Emilio Quezada, and our newest edition is a joint cardiovascular genetics program that's run in conjunction with Doctor Christina Theodores. We're excited to continue to grow and expand these programs. Our focus is family-based care, meaning that we strive to meet the needs of the entire family. So although our primary patient is pediatric. We know that genetics ultimately will involve all family members regardless of age. Our various programs offer comprehensive care from start to finish and include the following services. For patients that are experiencing cardiac symptoms, we offer clinical evaluation and diagnosis. When indicated, patients can have genetic counseling and we also help to coordinate genetic testing. We also understand that genetic test results can be confusing and burdensome for patients. We offer in-depth variant curation so that families understand the meaning of their genetic test results. We also offer second opinions for families that are seeking to understand more about their child's diagnosis if they receive this information from an outside institution. We also provide exercise recommendations that are driven by guideline-based screening, and for families where there's an actionable genetic test variant that's identified, we offer cascade testing for patients' relatives so that they can understand their risk and get plugged into the appropriate care. All of these are examples of the comprehensive family care that we provide. And Dr. Karen Austin is going to talk specifically about a case example that we believe illustrates this tailored care approach and highlights some of the features of our program. Hello, my name is Doctor Karen Austin, and I'm a pediatric electrophysiologist as well as the director of the inherited cardiac arrhythmias program at UCSF Benioff Children's Hospital. Today, I'd like to highlight a little bit more of the inherited cardiac arrhythmias program. On the right here, you'll see examples of the genetic diseases and syndromes that we more commonly manage. Obviously many of these are familiar long QT syndrome, Brugata syndrome, hypertrophic cardiomyopathy, but some of them might be less familiar, such as laminopathies, Dannon disease, and CPVT. This speaks to sort of the breadth of what we see in both the common and the rare diseases. We also manage patients who have either a personal history of sudden cardiac arrest or an immediate family history of sudden cardiac death. And in general, we think of our program as the intersection of three main components family, genetics, and expert clinical care. On the family side, one of the unique features that we provide personalized education to families, and this really allows them to have the agency to know more about their disease as they navigate the medical system. On the genetic side, Rachel was able to highlight a number of these features, but in addition to those we're able to sort of interface with world class research as well as getting involved in clinical trials related to these rare diseases. And finally, for expert clinical care, it's really the focus to provide evidence-based recommendations based off the wealth of knowledge and the most current up to date information in our field. And we thought the best way to go through this was to actually discuss a recent case. So this is an example of a teenager who was referred to us, having multiple episodes of having passed out. He also had EKGs which demonstrated a QTC greater than 500 milliseconds on multiple different occasions. There was also evidence of abnormal T wave morphology, which is illustrated on the slide. Now appropriately so, this patient was actually diagnosed clinically with long QT syndrome. And really actually had additional evaluation that included genetic testing. The genetic testing identified a variant of unknown significance in KCNH2. And unfortunately what was mentioned to the family that basically this did not account for the patient's phenotype, meaning it did not result in disease for him and therefore they were being referred to determine if additional genetic testing could be performed. From our perspective, this is really where we sort of thrive. We were able to kind of look at this variant which became much more suspicious when we investigated further, and one of the first things we enjoy doing is making sure that we do a very thorough genotype phenotype evaluation. And this led to having the patient undergo exercise testing. So in this scenario, we're able to use additional phenotypic information to determine whether or not this variant could potentially lead to a long QT phenotype. So here the patient started with an elevated QTC at baseline, which then appropriately shortened during exercise and then prolonged again during mid to late recovery. And this type of pattern is very typical for KCNH2 associated long QT syndrome. And really this led us to believe that in fact this certainly could be a pathogenic variant in this patient, and additional curation was warranted. And this is really where a detailed understanding of both the genes and the protein products associated with the syndromes that we investigate allow us to have a more nuanced interpretation of the genetic testing. So for KCNH2, this is a potassium channel that participates in the end of the action potential and is one of the major causes of long QT syndrome. More importantly, there are different domains in the protein. The pore-forming domain becomes a hot spot, particularly for missense variants, because it's very vulnerable to changes that can lead to a dominant negative effect. And if we're able to take all of these missense variants and kind of line them up on where the protein is, we can see that there's one area, particularly the latter part of the pore-forming domain, where they seem to cluster, and this is exactly where our patient's mutation was as well. So taken together, this information was highly suggestive that this could indeed be a pathogenic variant for this family. But we don't just stop there. Once we have suspicion that the variant could be pathogenic, we also understand the genetics of these particular diseases, and in long QT syndrome, it is almost universally inherited. Which means that likely one of the parents also carried the variant and could be at risk. We were able to get ECGs of both the mother and the father, and the mother's ECG also showed a significantly prolonged QT interval of greater than 550 milliseconds with similar abnormal Tweed morphology to her son. Further genetic testing in her identified she carried the variant, and then cascade screening also identified that a sibling carried the variant. And so, really taken together, the phenotypic evaluation we were able to perform, the additional variant curation that we're able to undergo, understanding the inheritance patterns in these rare syndromes, and then providing additional family assessment, all led us to the identification that It was almost certainly a pathogenic variant and was the cause of this child's long QT syndrome. But more importantly, it allowed us to then identify two additional family members who carried the variant and were at risk and to provide them treatment and further medical management moving forward. But our work doesn't stop at diagnosis. This is where we go the extra step and really involve patients in the educational components of their disease process. So what we do is we create personalized slide decks of information both on their disease, but more importantly, their specific genetic variants. And what this does is it really gives them both information and the agency to understand more about their disease and feel confident when they enter the healthcare system. Here are examples of the types of information that we give them background on the heart's electrical system. As well as sort of the function of how these different variants work, how they affect the proteins, we go through the signs and symptoms of each of these disease processes, and then we specifically go through their genetics and not just in general, but exactly where their genetic variant. is and what it causes. And then finally and perhaps more importantly, we're able to take this information and look through the literature and find any information available that we're able to share with the family. How does it behave in other families? What do we know about it? How can we predict what could happen moving forward? And we go through all of this with them in detail again to provide them information and then we also give them a copy of the slides, which then gets reevaluated every couple of years as new information becomes available. So now that we've gone through the details of the pediatric inherited cardiac arrhythmias program, I wanted to turn it over to my colleague Rachel Ferrell, who will review the comprehensive genetics program as a whole. Our program is unique at UCSF because we offer specialized expertise as well as comprehensive services so that patients really understand the complexities and implications of their genetic information. This allows for patients to really receive appropriate guidance so that we can best manage their condition. The overlapping breadth of our different teams really creates the pillars of our genetic program, all of which are intertwined and work collaboratively. An example of this is our strong relationship with our adult cardiovascular genetic counterparts. This relationship allows us to tap into their expertise as well as offer family-based care, not only for our patients but for their parents and other adult relatives. These services are available at both main institutions including our San Francisco and Oakland Children's Hospitals, as well as the various satellite locations that we have located in the northern portion of California. Regardless of location, patients have access to all of these services regardless of where they are. Providers can refer to our program by placing a. and Apex to pediatric cardiology and specifying the specific program that they would like to refer to. Providers can also enter a referral by calling the Access Center. The number is listed here. We'd like to thank you so much for your attention. We hope that this information has been helpful, and please reach out with any patient inquiries. We're very happy to help. Thank you very much.
