Genetic risk for aortic aneurysm and dissection

Experts have long recognized that the risk of aortic aneurysm and dissection is greater among people with certain inherited conditions, including Marfan syndrome. Now, progress is being made toward identifying genes associated with aortopathy in individuals who do not have such syndromes, including within the general population.

At Penn Medicine, researchers are moving closer to developing a risk assessment tool that could identify people at risk of life-threatening aortic aneurysms and/or dissections.

“Genetics play a large role in the risk of aortic aneurysm and dissection, and many patients would be candidates for genetic evaluation and genetic testing,” explains Staci Kallish, DO, a medical geneticist at Penn Medicine, in an episode of the Penn Medicine Physician Interviews podcast (see link below).

Exploring the genetic risk of aortic aneurysms and dissections

In a small subset of patients with aortic aneurysm or dissection, the risk can be traced to a pathogenic variant in a single gene. This includes several heritable connective tissue syndromes, including Marfan syndrome and Loeys-Dietz syndrome, which are known to increase the risk of aortopathy while also affecting systems throughout the body.

More recently, research at Penn Medicine and elsewhere has identified pathogenic gene variants that impact the arteries and increase aneurysm and dissection risk, but do not cause syndromes that extend beyond the vascular system.

Monogenic causes of aortopathy, in which the risk is attributed to a pathogenic variant in a single gene, are thought to occur in about 20 percent of people with a family history of aortic aneurysms or dissections. In the majority of people with aortic aneurysms and dissections, however, the causes are less straightforward.

“Most aortic disease is polygenic or multifactorial—a result of the cumulative impact of several or many changes in different genes, each of which has a smaller individual impact on disease,” Dr. Kalish says.

While to date there is no clinically available test to identify someone at increased risk of aneurysm and dissection due to polygenic causes, researchers at Penn Medicine have that goal in sight. Using large clinical and genetic datasets, researchers at the Penn Aorta Center are working to develop a polygenic risk score that folds an individual’s risk of aortic aneurysm or dissection into the genetic assessment of risk.

Such a tool could be used in combination with the aorta optimized regression for thoracic aneurysm (AORTA) score, which predicts risk based on known clinical risk factors such as age, sex, blood pressure, and heart rate.

“This combined model is better at predicting risk than clinical factors alone and is really the ultimate goal for determining who’s at risk for dissection,” Dr. Kallish says.

Diagnosing and treating aortic disease at the Penn Aorta Center

Although broad genetic testing for aortic aneurysm risk is not yet available for the general population, genetic testing plays an important role in evaluating and monitoring patients with aortopathy.

Good candidates for genetic testing include people diagnosed 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, with or without syndromic features.

At the Penn Aorta Center, patients meet with a team of cardiologists, cardiothoracic surgeons, vascular surgeons, geneticists, and other experts in diagnosing and treating complex aortic conditions.

Clinical consult and patient referral

Relevant practice information: Nimesh D. Desai, MD, PhD; Grace J. Wang, MD, MSCE, FACS; Wilson Y. Szeto, MD; Darren B. Schneider, MD; Kendall Lawrence, MD; Shang Loh, MD; Chase R. Brown, MD; and Alexander S. Fairman, MD, see patients at the Penn Aorta Center in Philadelphia, PA.

For a provider-to-provider consultation with the team at the Penn Aorta Center, please call 877-937-7366, or refer a patient online.

Associated Resources

Episode: Genetic risk for aortic aneurysm and dissection

Clinical genetics specialist Staci Kallish, DO, discusses this phenomenon, reviews ongoing studies to determine the risk for aortic aneurysm and dissection in the general population, and explains the protocols for genetic evaluation and testing candidates in at-risk populations.

Listen to this episode on Apple Podcasts, Spotify or YouTube Music.