MUSC researchers announce gene mutation discovery associated with EDS

July 14, 2021
Miss America in a lab coat pipettes samples under supervision
Camille Schrier, Miss America 2020, works with a sample under the supervision of lead researcher Cortney Gensemer. Schrier, who has EDS, came to tour the lab and learn about the gene mutation discovery the Norris team has made. Photos by Sarah Pack

When Miss America 2020, Camille Schrier, walked into the Norris Lab on the campus of the Medical University of South Carolina, she was among peers.

Not other contestants but other people who love science and are affected by an uncommon connective tissue disorder called Ehlers-Danlos syndrome, or EDS.

Schrier is perhaps not a typical Miss America. Her winning talent was a chemistry experiment, and she’s pursuing a Doctor of Pharmacy degree at Virginia Commonwealth University.

But it was the Norris lab’s focus on EDS that brought her to Charleston.

EDS is thought to affect 1 in 1,000 people. The syndrome is divided into 13 subtypes, which can cause hypermobile joints, a tendency for joints to dislocate, easy bruising, internal bleeding, heart valve problems and more. Because connective tissue is found throughout the body, the disorder can cause problems anywhere in the body.

“It's much more than a structural disease. It's a full-body disorder,” said Roman Fenner, a Davidson College student interning in the lab for the summer.

Mutations in some 20 genes have been found to be responsible for some of the subtypes. But the gene associated with the most common subtype, hypermobile Ehlers-Danlos syndrome, or hEDS, has remained – officially – unknown.

But it is not unknown to the researchers gathered in the Norris lab.

Russell “Chip” Norris, Ph.D., a professor in the Department of Regenerative Medicine and Cell Biology, and his team believe they have identified a gene mutation associated with hEDS. They’re currently running tests with a model to confirm their findings, which they expect to write up within six months – hopefully sooner.

“I think one of the coolest things is, when we publish, we’re going to have five people with the disease as authors on the paper. And it’s going to be a groundbreaking paper in terms of EDS research.”

Cortney Gensemer, lead researcher

They’re well aware of how eagerly the hEDS community is awaiting their findings: Lead researcher Cortney Gensemer and the four undergraduate summer interns are all EDS patients themselves.

“I think one of the coolest things is, when we publish, we’re going to have five people with the disease as authors on the paper. And it’s going to be a groundbreaking paper in terms of EDS research,” said Gensemer, a fourth-year doctoral student.

As much as the discovery is a huge breakthrough, it is still only the beginning of more research, the team explained. Even so, people with EDS want that validation that there is a physical cause behind their constellation of symptoms, which patients often deal with individually for years before someone finally realizes the seemingly unrelated ailments all point to EDS.

“Everyone who has EDS is so hyper-focused on this gene because it’s tangible evidence of what we have. Because in many cases this can be an ‘invisible’ illness, and you have a lot of doctors saying, ‘It’s in your head, theoretically you shouldn’t be in a lot of pain.’ So at least for me, I’m looking forward to having that proof,” said Sofia Luzbetak, a summer intern from the University of California San Diego.

Schrier agreed. Because EDS generally isn’t life-threatening – at least not with the same immediacy as cancer or other diseases – it doesn’t get as much attention, she said.

Camille Schrier listens as she wears a specially made Norris Lab lab coat that has her name and Miss America 2020 embroidered on it 
Medical students are sometimes told that when they hear hoofbeats, they should look for horses, not zebras. In other words, they should look for the most common and obvious diagnosis. EDS patients consider themselves the medical zebras, because they actually have the uncommon diagnosis. The Ehlers-Danlos Society has taken the zebra as its mascot, and Camille Schrier wore zebra stripes to the Norris lab.

“I'm so thrilled to see a lab focus on it and put the time and effort and money toward it,” she said.

Before doing a social media Q&A with Gensemer and Norris, Schrier toured the lab and even got to put her lab skills to use, helping to prepare samples for gene sequencing.

“It’s been incredible, as someone who not only loves science and scientific research but is a patient affected by EDS, to be able to watch what I learned as a science student and as an undergraduate researcher be applied to solve a problem for a disease I have,” she said of what she’d seen.

Birth of a research project

EDS is not something that Norris is known for. He’s spent most of his career investigating the genetics of cardiovascular diseases, including something called mitral valve prolapse, in which the mitral valve flaps don’t close properly with each heartbeat. But three years ago, he offered a blanket invitation during orientation for any of the new doctoral students to come see him for advice. Gensemer took him up on the offer.

Gensemer hadn’t started her graduate program with the idea of studying EDS.

“Studying my own disease wasn’t something I thought was feasible. There was no one studying it, so that was not something I went to grad school thinking I would do,” she said.

In fact, when she walked into Norris’ office for the first time, she didn’t know what she wanted to do.

“I just walked into his office and said, ‘Hey I'm scared. I don’t know what to do here,’” she recalled.

They started talking about his research, and she volunteered that mitral valve prolapse was a common problem for people with EDS. Norris asked her which gene was responsible for hEDS, and she responded that no one knew. “Pretty quickly in that conversation it turned into ‘Do you want to rotate in the lab and find the gene?’” she said.

Gensemer began working in the lab on mitral valve prolapse and, on the side, sequencing the genes of a large family with multiple members with hEDS.

“From a scientific perspective, it was probably a dumb decision,” Norris said. Others had thrown time and money at the question before, without results, he said. But they had a large family to work with. Norris looked at the odds of finding the gene with the information they had and decided that, while the odds weren’t great, it was at least worth taking a shot.

Miss America listens as researcher Chip Norris speaks and gestures 
Dr. Russell 'Chip' Norris talks about the research happening in the lab.

The researchers had complete exomes from two distant relatives to work with. The exome is the part of a person’s genetic material that contains protein-coding genes, and scientists believe that it’s the source of the majority of genetic diseases.

The sequencing showed that the two individuals shared 75,000 uncommon genetic mutations.

That’s a lot of mutations to sift through. But, Norris pointed out, “uncommon” doesn’t necessarily mean disease-causing.

“We all have literally hundreds of thousands of changes that are not common, but none of them are really causing anything,” he said. A mutation could be considered uncommon if it’s found in only 10% of the population, but since 10% of the population doesn’t have hEDS, it follows that that gene wouldn’t be the cause of hEDS.

Gensemer and Norris enlisted the help of Joseph Delaney, Ph.D., a cancer geneticist in the Department of Biochemistry and Molecular Biology, who helped them whittle the list down to 10 candidates.

“He sent us back the information, and he said in genetics, you rarely have these ‘aha!’ moments, but I think that this gene is the ‘aha,’” Norris said.

Norris and Gensemer then sequenced the 10 suspect gene mutations across the family, looking for a gene mutation that would show up in every individual with hEDS.

And they believe they have found it.

But they’re not stopping there. There are almost certainly more genes involved, and the researchers wanted more samples to work with. To do that, they needed to establish a patient registry, in which patients would voluntarily send saliva samples for testing. The registry, driven by four clinical coordinators at the South Carolina Clinical & Translational Research Institute (SCTR) and Natalie Koren in Norris’ lab, opened in December and was immediately inundated with sign-ups. “In one day, we had the largest registry for hEDS in the world,” Norris said.

“I remember that day – I went home and turned off my email because it just kept – ding, ding, ding,” Norris said.

Along with the patient registration emails came the personal stories of people desperate for answers.

Search for answers

It often takes years, even decades, before patients receive a diagnosis of EDS. Diagnosis is based on a checklist, but getting to that checklist requires someone who can connect the dots of disparate symptoms.

“If you have mitral valve prolapse and you’re seeing a cardiologist, and you dislocate your shoulder and you’re seeing an orthopedic, and you have GI issues and you see a GI doctor – there usually isn’t someone putting all that together. So patients will spend a really long time thinking they have all these different health issues – which they do have – but not know it’s part of the syndrome,” Gensemer said.

And many medical professionals remain unaware of how severely EDS can affect people, she said. 

“There is this misconception with a lot of doctors that EDS is just being double jointed, and that these patients aren’t suffering with chronic pain, hospitalizations and surgeries,” she said.

With the registry growing, Gensemer and Norris needed more help in the lab. He brought Rachel Biggs, an incoming Ph.D. student, onto the project. But then, instead of going the usual route of hiring a couple of lab techs to round out the team, Norris decided to find people at the cusp of their careers who were truly passionate about EDS.

“We need to build the community of people who understand the disease. Who better to do it than those with the disease?” he said.

He decided to implement a summer intern program for college students with EDS. After a nationwide search, Fenner, Luzbetak, Katherine Singleton from Clemson University and Deatra Bear from Colorado Mountain College were selected to come to Charleston.

people sit on sofas and chairs in a pleasant living room along with two young women wearing tiaras 
Members of the hEDS research team relax along with Miss South Carolina Julia Herrin and Miss South Carolina Teen Dabria Aguilar. The four undergraduate interns are living in the house near the peninsular MUSC campus for the summer.

Bear, who plans to go into nursing, said she’s eager to get the word out about EDS. And she’s excited about the research, which could lead to a simple blood or saliva test to diagnose EDS.

Early diagnosis is critical. Although there is no treatment as of yet, knowing that they have the disorder means patients can manage their symptoms through proactive physical therapy and lifestyle choices.

“For me as a kid, playing lacrosse and running competitively weren’t the best choices,” said Gensemer, who’s since undergone numerous orthopedic and neurosurgeries.

Luzbetak was placed in gymnastics and dance when she was young because she was so flexible.

“I caused irreversible joint damage,” she said.

When she hit puberty, she began deteriorating quickly. Her joints hurt so much that she was practically bedridden, yet doctors said it was just growing pains, she said. She finally got a doctor who suspected EDS but didn’t feel qualified to make the diagnosis. Her family had to travel out of state to seek care.

“I ended up not being able to finish high school. I had to get my GED because the next four years were filled with constant doctors' appointments and hospital visits,” she said.

“We need to build the community of people who understand the disease. Who better to do it than those with the disease?”

Russell 'Chip' Norris, Ph.D.

Bear, too, had to travel out of state for a diagnosis – all the way to Florida from Colorado. Her symptoms primarily manifest as gastrointestinal, and for that reason, doctors first suspected Crohn’s disease. Because her stomach doesn’t digest well, she has a feeding tube to ensure she gets proper nutrition.

Gastrointestinal issues aren’t talked about as much in relation to EDS, she said, yet they’ve discovered that 80% of the people in the patient registry report some GI issues.

Fenner was diagnosed at age 9, after his more severely affected mother and sister were diagnosed.

“She sat me down and said, ‘I know this is going to be hard to hear, but you can’t play soccer anymore, you have to stop taekwondo, you can’t be a Boy Scout – all these things are going to be really bad for your body.’ So I turned to music and now I'm a double major in biology and music,” he said.

Katherine Singleton, a Clemson student, was only recently diagnosed. She, too, did gymnastics and dance in addition to track, where coaches put her on hurdles because they were amazed at how easily she could swing her leg up and over.

overhead shot of researchers students and interns gathered in the lab 
Graduate students and undergraduate interns meet with Miss America 2020, Camille Schrier in the Norris lab.

But Singleton began experiencing extreme fatigue in high school. She would sleep and sleep and yet never feel better. Fatigue is a symptom of EDS, but it’s probably better known as a symptom of depression, and that’s what her pediatrician referred her to a psychiatrist for. This fed into a negative cycle, she said. Doctors were telling her she was depressed, and she wasn’t getting treatment for her actual condition and was still tired, which then actually did start to make her feel depressed, which then reinforced the doctors’ original assessment.

When she finally discovered the diagnostic checklist, she brought it with her to several specialists’ visits but found that most doctors didn’t feel confident in diagnosing her. Now, not only does she have a diagnosis, but she’s contributing to the scientific knowledge about her condition.

Schrier said she found it empowering to see the group tackle this research question, particularly knowing how little attention it gets. She has been open about her diagnosis in hopes of bringing more awareness of and attention to EDS, even encouraging her followers to donate to the Norris lab, if they feel moved to do so.

Norris has high hopes for what the next three to five years will bring in terms of discovery and, possibly, treatment.

“By identifying a cause for the disease, we can now begin understanding the disease more thoroughly,” he said. “This will help us diagnose earlier and provide clues for treatments. We remain optimistic that our discoveries will provide continued hope for those with hEDS and a better quality of life with less surgeries and less pain.”

EDS research

Miss America 2020, Camille Schrier, visited the Norris lab at MUSC to learn about research into hypermobile Ehlers-Danlos syndrome.