Gene Screen

Gene Screen

A serendipitous crowdsourcing project changed the trajectory of Andrea Meredith’s research, connecting her directly with patients of a mysterious disease.

By Melanie Padgett Powers

One night just before bed in August 2018, Andrea Meredith, PhD, was reading the New York Times Magazine on her iPad when she came across an article about a six-year-old girl in South Dakota named Kamiyah who had a mysterious disorder.

Over 300 times a day, the little girl would fall or slump forward, with large portions of her body paralyzed. An episode would last anywhere from three to 20 seconds. Then, suddenly, she would pop back up and resume whatever she was doing. The article mentioned that Kamiyah had paroxysmal dyskinesia, a type of movement disorder. But the cause was unknown.

Kamiyah’s genome had been sequenced at the National Institutes of Health (NIH) two years earlier, but her parents had not been contacted with any results. Then, in the middle of the New York Times reporting, Kamiyah’s mom heard from the NIH. The results showed a gene mutation. That first article Meredith was reading, however, did not name the gene.

The symptoms began to sound eerily familiar to Meredith, an associate professor in physiology at the University of Maryland School of Medicine. She realized the article could be describing the gene and ion channel her lab was focused on every day. “I turned to my husband and sort of said it for the record: ‘Hey, Jim. This looks like a BK channel mutation, but they don’t name the gene. It’s torturous.’”

The story that Meredith had stumbled upon was part of a collaboration by the Times and Netflix to crowdsource potential answers to undiagnosed mysterious disorders in individuals. In Kamiyah’s case, the cause of her paroxysmal dyskinesia was found during the article’s reporting, but the underlying disease didn’t have a name, and her parents had not heard of anyone else who had the same gene mutation.

Two and a half weeks later, a follow-up article about Kamiyah named the gene mutation. “They said the gene is KCNMA1,” Meredith says. “I read the follow-up article right before I got into the car [for work]. I have this super-long commute. Then I was trapped in the car for almost two hours, thinking, ‘Oh my gosh, that’s my ion channel.’”

Meredith emailed the Times the next day. That exchange would change the trajectory of her research. She would appear in a Netflix documentary, connect with families linked to her research and launch a foundation.

A Life’s Work

Meredith did her postdoc at Stanford University in California, where she began studying the physiology of ion channels. That’s where she made the first genetic deletion of the KCNMA1 gene.

For the past 13 years, she has been running her own lab at the University of Maryland, immersed in the science of KCNMA1, which encodes the BK ion channel (BK stands for “big potassium”). The channel regulates how much potassium exits a cell, a process that controls numerous neurological processes.

Before the Times article, Meredith’s team was studying how the BK channel was used for information coding using the circadian clock as the exemplar. “For example, some people are morning people; some people are evening people,” she says. “And there is a variety of genetic bases for that. We were interested in understanding whether changing BK channel properties as a result of natural occurring genetic variation between individuals would influence how the brain’s clock tells time.”

When Meredith came across Kamiyah’s story, she wasn’t surprised that people were affected by a KCNMA1 gene mutation. A 2005 research study in Nature Genetics was the first to report on a family affected by a different KCNMA1 mutation. But that family in China wasn’t identified. “It would never have occurred to us that we could have a personal interaction with the patients. It was just a pedigree in the literature,” Meredith says.

The Times replied to Meredith’s email, requesting a Skype interview, which is when she learned about the Netflix show. She actually ended up doing three Skype interviews, and Netflix even sent a film crew to film her in her lab and at her house. “It was a bit nerve-racking,” Meredith says. “They didn’t have a scientist in the crew, so it felt like a free-for-all in terms of what they might want. I was so much more prepared to present the science, obviously, but it was very clear they wanted the emotional side of things.”

They did take after take, as they encouraged Meredith to use simpler language for a lay audience. “They wouldn’t let me use big words like ‘ionic currents’ or ‘action potentials.’ They asked more questions about how I ‘felt’ about Kamiyah and other kids with KCNMA1 mutations.”

However, she was intrigued by the process. “It was the most interesting to see the end product because after all the takes and retakes … it wasn’t clear to me that any of it (especially scientifically) was even remotely going to make sense. I think they did a great job piecing together the story, both in the whole episode and how our little piece of the science fit into it.”

Through the reporting team, Meredith was connected to Kamiyah’s family, who sent her the little girl’s genetics report. As Meredith’s research team examined the findings, the researchers realized they had already studied Kamiyah’s mutation. They had found the sequenced gene in a public database curated by the NIH, but it was anonymous. Because it wasn’t linked to Kamiyah or to a disease, Meredith’s team considered it an orphan mutation. “We knew exactly what her mutation did, and we knew that it was stronger than any other mutation that we had seen before,” she says.

A Netflix Debut

In August 2019, Netflix released a seven-part documentary called “Diagnosis.” Each episode outlines the crowdsourcing efforts to diagnose someone’s mysterious symptoms.

Meredith appears in episode four, “Looking for a Village.” In a Skype interview on the show, she describes her reaction to reading the initial article: “All of a sudden, everything I’d gotten into science for and started studying this particular channel for could potentially be linked to a human patient that I could help.”

In an especially poignant moment in the documentary, Meredith makes another connection—this time, a maternal one. During a Skype call with Kamiyah’s mom, Breteni, Meredith gets choked up as she describes her dedication to this research. She told The Physiologist Magazine, “At first I was a little bit ashamed because scientists are supposed to have a stiff upper lip, but my daughter is just about the same age as Kamiyah. I realized the gift of having a healthy child and the agony of watching your child have these baffling attacks that you can’t control.”

An Urgent Mission

Meredith says she had trouble sleeping after hearing about Kamiyah: “I was really haunted.” Through Facebook, other families with kids like Kamiyah started popping up. So far, fewer than 50 people in the world have been identified with the disorder.

“I felt a sense of urgency that we really needed to kick everything in the lab into overdrive and start figuring out how to understand what their mutations were doing and how they were producing symptoms,” Meredith says.

First, she gave the disorder a name: KCNMA1-linked channelopathy. “The only thing that defines this disorder—because we don’t really know anything about it mechanistically—is the fact that people that present with these symptoms have mutations in KCNMA1,” she explains.

Meredith also co-founded the KCNMA1 Channelopathy International Advocacy Foundation with Sotirios Keros, MD, PhD, a pediatric neurologist and epilepsy specialist at the University of South Dakota. The Foundation serves as the home base, educating and connecting families with each other and the research community. The team is also developing a patient registry. In the future, the Foundation plans to develop patient education resources, raise money for research and sponsor meetings and conferences.

Crowdsourcing Cautions

While crowdsourcing in this case connected families who had felt all alone, Meredith urges caution with using crowdsourcing in health care.

“I actually think that there’s a potential danger in this, and the danger is not that the answer will be wrong because I think it could be relatively straightforward to sort out the evidence of whether a diagnosis is right or wrong,” she says, “but the danger, in my opinion—and I’ve seen this in the patient population that we’re now interacting with—is that as soon as you come up with a gene mutation or a candidate diagnosis, the patients think there’s a cure.

“They hope that because a gene mutation has been discovered that that means that my lab or somebody else’s lab tomorrow, the next day, fairly soon, is going to wave a magic wand and have a precision medicine answer for their child, and it doesn’t work like that.”

In fact, knowing these kids have a specific gene mutation hasn’t changed the treatment plan or led to new therapies yet. Their day-to-day lives remain the same. Meredith says parents with children who have KCNMA1-linked channelopathy should be trying the standard anti-seizure and dyskinesia medications for their kids.

What has changed is that Meredith’s lab is actively making mutations in transgenic mouse models with CRISPR using these kids’ specific mutations. “We basically switched all of our resources over to understanding how these patient mutations … change the channel properties and then how they might produce symptoms in an animal model,” she says. “We really put every single resource that I have in my lab into this, and our next goal is to get a grant funded on it. NIH support is so critical to projects like these.”

Her research team is trying to figure out how the mutation produces symptoms—and how and why some of those symptoms differ from patient to patient. While nearly all of these patients have some sort of movement disorder and a seizure disorder, the types of seizures vary widely. In addition, it’s unclear whether a host of secondary symptoms are linked to the mutation.

“The most important thing to discover is not necessarily how the mutations change the channel properties but how those mutant channels produce the symptoms of the disease,” Meredith says. “The forefront of understanding KCNMA1-linked channelopathy is really understanding the brain and neuromuscular mechanisms of the seizure and the movement disorder that these mutations produce.”

While the disorder is found mostly in children, Meredith thinks that’s circumstantial. Adults with the disorder have probably gone undiagnosed because whole genomic sequencing wasn’t available when they were kids and KCNMA1 wasn’t yet a part of any genetic testing panel. Instead, the adults were likely diagnosed with an unnamed seizure disorder and put on seizure medication. And that’s fine for now, Meredith says, because without a cure for KCNMA1, treating the symptoms is the recommended course.

Meanwhile, Meredith and her lab press on to learn more about KCNMA1-linked channelopathy, with the hope that better treatment or a cure may one day be found. “I’ve always been very focused, and very mechanistic, but I would certainly say that what we feel now is a sense of pressure and a sense of urgency—that it’s not just intellectual anymore,” Meredith says. “There are real kids whose daily lives could be changed if we understood more about the mechanisms of this disorder.

“I feel really committed—and I don’t want to be overstating it—but it came to the right person. I’ve always worked on this channel, and if this is the contribution that I make until the end of my career, I would be completely satisfied. It feels like everything that I did up until now prepared me for meeting these patients and being ready to help them.”