Marfan patients team up with researchers to catch their silent killer

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The world’s undiagnosed Marfan patients often go through life unaware of the hidden killer lurking in their DNA – a gene variant which may lead to sudden death at any moment via an aortic dissection. Currently, there is no therapy available to counteract this disastrous aortic event, so patient awareness of their condition is key to prevention. To learn more about Marfan syndrome and improve diagnosis, our project needs patients to enroll online in our research cohort. In this way, patients themselves can help us contribute to new therapies and avert sudden deaths.

Robin and Sam, a happy pair of young siblings, are playing basketball with their friends when their world comes crashing down. Suddenly, Robin experiences heavy chest pain and starts losing consciousness. An ambulance rushes Robin to the emergency room. The verdict: an aortic dissection – a tear has formed on the inside of his aorta, where his blood can rush through. A complicated emergency surgery is needed to save his life.

After a difficult but successful surgery, genetic testing diagnoses Robin with Marfan syndrome, a rare genetic disease that affects connective tissue. People with Marfan syndrome are usually tall and thin with long limbs, fingers, and toes, and often have other symptoms like bad eyesight and aortic dilation, which is what resulted in Robin’s aortic dissection.

Marfan syndrome is caused by a genetic variant in connective-tissue gene fibrillin-1 (FBN1). Robin inherited this disease from his mother, who inherited it from her father, but neither of them had any idea they were harboring a life-threating disease.

Why Robin? Unraveling the genetic mystery

Why did young Robin’s aorta rupture, while his mother and grandfather remain healthy despite carrying the same gene? This question is what drives our research project GEMS (Genome-wide Epistasis for cardiovascular severity in Marfan Study). We hypothesize that there must be other factors in the DNA of our patients that influence aortic dilation and rupture. We call these factors genetic modifiers.

To research these genetic modifiers, we require a large patient cohort of people carrying the disease-causing FBN1 variant. For this, we teamed up with the Belgian patient organization Foundation 101 Genomes. Together we designed an online platform where Marfan patients can enroll themselves into our study from all over the world.

“Why did young Robin’s aorta rupture, while his mother and grandfather remain healthy despite carrying the same gene?”

This collaboration makes our research fully patient-driven through a novel and innovative web-based concept. After online enrolment, patients receive a saliva kit to donate their DNA from a saliva sample to our database. They can register their own medical features (such as aortic diameters), or they can authorize their treating physician to share their medical data with us on their behalf.

In the second phase, we rank  study participants based on their aortic status to define our ‘extreme-end patients’. At one end of the spectrum, these are older patients who still have a healthy aorta; at the other end are younger patients who are already showing signs of aortic dilation.

How to study a living person’s aortic cells?

Unfortunately, studying the aorta of living patients is nearly impossible, as we don’t currently have suitable methods for easy and safe access to the aorta. To overcome this issue, we instead use an innovative method to study the aortic cells of patients in the lab. How do we do this?

First, we reach out to the ‘extreme-end patients’ in our cohort to request a blood sample. From this sample, we can isolate their white blood cells, and reprogram them into induced pluripotent stem cells in our lab. These cells that are like embryonic stem cells of the patient themselves, meaning that they can grow into any tissue of that specific patient. Making use of this concept, we can guide the cells into becoming aortic muscle cells.

“The complexity of the aortic cell model helps us to obtain data to see what is happening in the cell in real time.”

These patient-specific aortic cells enabling us to study the cells of Marfan patients with healthy or dilated aortas to see what is causing the difference in disease characteristics. The complexity of the aortic cell model helps us to obtain data to see what is happening in the cell in real time. We can combine this information with the patient’s DNA to identify genetic modifiers preventing or worsening the aortic dilation caused by Marfan syndrome.

The patient benefit circle

The goal of our project is to find a genetic modifier that can determine likely disease severity in Marfan syndrome. If we are able to identify this, patients would benefit in two ways. Firstly, physicians would become better able to estimate the risk for each patient, meaning high-risk patients would get a closer follow-up, while protected patients would need to be monitored less frequently. Secondly, the identification of modifiers may lead to new therapeutic strategies. For example, a protective genetic modifier may be mimicked by medications to protect patients without that specific modifier already embedded in their DNA.

Read this previous SciMingo article to learn about Stargardt disease: a genetic condition that leads to vision loss

By taking part in our study, Marfan patients can actively participate in progress for themselves and their loved ones. The potential benefits are huge, allowing people like Robin to live happy, healthy lives without fear of a ticking time bomb in their chest. So, if you are a patient with Marfan syndrome (or know someone who is), please sign up to our research cohort and help us complete this circle.

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