Melanie Cole, MS (Host): Welcome to the podcast series from the specialists at Penn Medicine. I'm Melanie Cole. And today our discussion focuses on aorta genetics. Joining me is Dr. Staci Kallish. She's an Associate Professor of Clinical Medicine at Penn Medicine. Dr. Kallish, it's a pleasure to have you join us today. I'd like you to start by telling us a little bit about your unique role at the Penn Aorta Center.

Dr. Staci Kallish: Sure. And thanks for having me. So, I'm a medical geneticist. So, my role in the Penn Aortic Center is in evaluating patients with aortic disease for possible underlying genetic causes. This usually involves a detailed history, not just of their aortic disease, but of their full medical history. We also take a careful family history and then complete a thorough examination, looking for possible features of some of these inherited conditions. We can then offer genetic testing to our patients to identify potential underlying familial conditions that could be contributing to their aortic disease.

Host: What an interesting field you're in, Dr. Kallish. So, we've known for some time that about 20% of aortic aneurysms and dissections can be attributed to certain heritable conditions, and that diagnostic genetic tests are available for these populations. So, what are these conditions? How have they helped us to understand the genetic landscape for aortic disease?

Dr. Staci Kallish: So, medical genetics is really interesting. And you're correct, we can identify a monogenic or a single-gene cause that contributes to about 20% of individuals who have familial aortic aneurysms and dissections.

Some of these conditions are syndromes. Marfan syndrome is certainly the most well-known, but there are other syndromes like Loeys-Dietz syndrome. These affect not just the aorta, but other body systems, depending on the condition, and possibly other arteries beyond the aorta as well. There are also non-syndromic conditions, conditions that impact the aorta and sometimes other arteries, but not body systems beyond the vasculature. Identifying an underlying monogenic cause, when we’re able to, lets us know how to manage patients. So, it tells us which blood vessels to monitor, what our surgical threshold should be for the aorta, and then it also gives us information to screen the patient's family members to determine who is at risk and needs evaluation.

Still, it's important to understand that the variants causing monogenic conditions are rare and more common variation in the same genes and in other genes also has impact on the aorta.

Host: What we're learning more is the remaining 80% of aneurysms and dissections occur in people who don't have a known heritable cause. Do you have a suspicion that genetics plays a role in aortic disease in this wider population? Is it random? Tell us about that.

Dr. Staci Kallish: It's a great question. And as a geneticist, I think that our genetics play a role in everything that happens in our body. So, again, the conditions that we just discussed are monogenic, or single-gene disorders, where a rare abnormality in a single gene has a large impact on clinical features, in this case, on the risk of aortic disease.

Most aortic disease though, and most disease in general, is polygenic or multifactorial. So, this refers to the cumulative impact of several or even many changes in different genes, each of which may be common or may be rare in the population but has a smaller individual impact on disease.

Host: You mentioned mutations found in Marfan's and Loeys-Dietz syndromes. Are some of those Mutations found in non-syndromatic individuals? Tell us a little bit about that.

Dr. Staci Kallish: So pathogenic variants, which we used to call mutations, in the genes associated with Marfan syndrome or Loeys-Dietz syndrome cause syndromic disease. But there are other variants in these genes that can also cause non-syndromic disease. So, we do see some individuals and families who have pathogenic variants, changes in genes that we clearly know are disease-causing in patients who have aortopathy or other vascular disease, but don't have any of the musculoskeletal, eye, or other findings that we see in the syndromic forms. This is why it's important to consider genetic testing for aortopathy, even in individuals without syndromic features.

Those who are good candidates for genetic testing are those with aortic or arterial aneurysms at a young age, those with rapidly progressive or multiple aneurysms, and those with a family history of aneurysms or dissections, even if there are no syndromic features.

Host: Are there tests available to find genetic variants for aortic disease in the general population? I think this is an important question for primary care.

Dr. Staci Kallish: So, we do not yet have clinically available tests to identify these risks, but research is ongoing in this area, including at Penn Medicine. These studies use large sets of data, so both clinical and genetic information from many individuals in an anonymized manner to determine genetic changes associated with risk of disease, in this case, with risk of aortic aneurysms and/or aortic dissection.

Unlike in the conditions we talked about a bit ago, these variants associated with polygenic disease may be more common in the population but also have smaller effects on aorta size or risk. An individual can have several or even many of these smaller risk factors or may have protective variants as well.

We can combine these to create what's called a polygenic risk score, which estimates an individual's risk of developing an aortic aneurysm or dissection. This work will likely lead to exciting advances in our management of individuals with aortic dilation but is not yet clinically available.

Host: So, what have ongoing investigations discovered thus far? Are we getting any closer, Dr. Kallish, to being able to determine an individual's personal risk for aneurysm or dissection? And I'd like you to tell us about the aorta optimized regression for thoracic aneurysm or aorta score.

Dr. Staci Kallish: Sure. So, the aorta score, or as you said, the aorta optimized regression for thoracic aneurysm score, uses a combination approach. So, it uses a polygenic risk score for aortic disease combined with clinical factors to create an individualized clinical prediction model. The clinical factors include parts of an individual's medical history, which are also known to have impact on risk of aortic aneurysm or dissection, such as age, sex, blood pressure and the presence of hypertension, and heart rate.

By combining these known clinical risk factors and genetic risks from a polygenic risk score, we can better predict who is at risk for aortic aneurysm and, importantly, aortic dissection, which allows for more frequent imaging and earlier medical intervention to impact morbidity and mortality.

The combined model with polygenic risk scores is better at predicting risk than clinical factors alone, and this is really the ultimate goal to determine who's at risk for dissection and other events, and then to prevent or manage these for the best health outcomes. And while this type of testing isn't available in our clinics yet, we're getting closer to being able to use this as part of our genetic assessments of risk.

Host: This is such a great conversation, really an interesting topic as well, Dr. Kallish. As we wrap up, how would a referring provider obtain more information or referring a patient to the Penn Aorta Center and what would you like the key takeaways to be about aorta genetics?

Dr. Staci Kallish: So, the key takeaways are that genetics play a large role in the risk of aortic aneurysm and dissection, and that many patients would be candidates for genetic evaluation and for genetic testing. Part of the Penn Aorta Center includes evaluations with cardiologists, cardiothoracic surgeons, and vascular surgeons as needed, and also genetic evaluation. Referring providers can go to the Penn Aorta Center's website for information or can go to www.pennmedicine.org/refer to refer a patient.

Host: Thank you so much, Dr. Kallish, for joining us today. And to refer your patient to the Penn Aorta Center, please call our 24/7 provider-only line at 877-937-PENN or you can submit your referral via our secure online referral form by visiting our website at pennmedicine.org/referyourpatient. That concludes this episode from the specialists at Penn Medicine. I'm Melanie Cole.