How Genome Sequencing Creates Communities Around Rare Disorders

The last two years have been a whirlwind of good news for Lilly Grossman. She graduated high school and successfully applied for college, where she'll be majoring in English. She went to her prom and was crowned homecoming queen. She edited her school newspaper. She even visited the White House and met Barack Obama. But the two most important aspects of Lilly's recent life seem far more mundane to other people. She has been sleeping. And she has been planning for a future that, for the longest time, her parents doubted she would have.

Ever since she was a small child, Lilly's body has been wracked by painful and relentless muscle tremors. At first, they only happened at night, robbing her and her parents of anything but the most fleeting stretches of sleep. Then, they crept into the daylight hours, leaving her with muscle weakness and balance problems, and making her dependent on walkers or wheelchairs.

No one knew what was wrong. The family bounced from one physician to another, each one offering a different but equally wrong diagnosis. Her parents, Steve and Gay, compiled a dossier of medical records, thick with the results of unfruitful and often-painful tests. Life was hard, birthdays especially so. With the most likely diagnosis being some kind of mitochondrial disease—a class of conditions that often come with poor prognoses—Steve and Gay felt that the sand was draining from their daughter’s hourglass.

Everything changed when the family learned about a study called IDIOM, led by Eric and Sarah Topol at the Scripps Translational Science Institute. IDIOM was an attempt to diagnose people with “serious, rare and perplexing health conditions” by sequencing their entire genomes and uncovering the faulty genes that presumably lay behind their problems. Lilly fit the bill perfectly. She became the first IDIOM volunteer—and its most successful by far.

Within Lilly’s DNA, the Scripps team found a mutation in a gene called ADCY5, which is highly active in parts of the brain involved in coordinating movements. Based on these results, Lilly's doctor decided to try her on a drug called Diamox, which had helped the only other known family with faults in ADCY5 (more on them later). When Lilly tried the drug, she started sleeping soundly for the first time in years.

When I first spoke to the Grossmans in 2013, they had just celebrated Lilly's 16th birthday. “That was the first one where we’ve known that Lilly will be here on her next one,” Gay told me. “That alone was worth the sequencing. It bought us time. We always thought there wasn’t much time.”

I caught up with them again last month. With Lilly about to start at college, their spirits are still up—and for reasons beyond simply buying time. Lilly's case has acted as a magnet for others with the same mutation. Families with the same problem read about Lilly’s case and contacted the Grossmans. Doctors and geneticists looked at their own patients and saw a new explanation behind puzzling symptoms. Before, there were isolated pockets of people around the world, dealing with their own problems, alone for all they knew. Now, there’s a community.

This is a trend. Take Matt and Christina Might. Their story, as recounted last year by Seth Mnookin in The New Yorker, has many of the same leitmotifs as the Grossmans’: a child, Bertrand, who suffered from a movement disorder at an early age; a long diagnostic odyssey of punishing tests and false leads; and a sequencing study that finally identified the gene behind his condition—NGLY1.

At the time of Bertrand's diagnosis, no one knew of any other patients with diseases caused by NGLY1 mutations. Those cases only came to light after Matt recounted the family's saga in a 5,000-word blog post, which then went viral. Within months, the Mights had been contacted by parents who had recently learned that their children had NGLY1 mutations, and scientists and doctors who had found (but often ignored) the same alterations in their patients' DNA.

The Grossmans’ story followed similar themes, with slight variations. For a start, at the time of Lilly's diagnosis, ADCY5 mutations had been implicated in disease. In 2012, Wendy Raskind at the University of Washington had pinpointed the gene as the culprit behind a movement disorder affecting a German family, whose symptoms—jerky, involuntary spasms of the face, head, neck and arms—were similar to Lilly's. Raskind called the condition “familial dyskinesia with facial myokymia” (FDMD) and although she had been studying it for 11 years, she didn't know of any other cases besides that one family.

Then, she learned about Lilly when the IDIOM researchers contacted her. Soon after, colleagues at the University of Washington told her about a third patient—an 18-year-old woman who had exactly the same mutation as Lilly, and similar if slightly milder symptoms. These unrelated cases assured Raskind that she was right: ADCY5 was indeed the gene behind FDFM.

Meanwhile, the Grossmans were making their own contacts. In March, Gay got a call from a woman who had just learned that her daughter had an ADCY5 mutation. She had searched for the gene, found the story I had written for National Geographic, looked up the Grossmans on Facebook, and found a page that Gay had made about ADCY5. “When she called me, she had just gotten her daughter's diagnosis that day,” says Gay. “Her story... it could have been me talking.”

More and more people made contact through the same means, often within 24 hours of getting a diagnosis. The Grossmans quickly found kindred spirits in the USA, Canada, Australia, and the Netherlands. In June, the Grossmans even set up a joint meeting between patients and researchers, to coincide with an international conference on movement disorders that was taking place in San Diego. Eight families attended, as did half-a-dozen clinicians.

With Lilly off to college, Steve and Gay are spending even more time on advocacy. They want to set up a registry to collate the details of everyone affected by ADCY5 mutations. They’ll be reaching out to organizations that represent disorders that Lilly was initially misdiagnosed with, like the United Mitochondrial Disease Foundation and the Cerebral Palsy Foundation, so that they can consider if their patients might actually have Lilly’s disorder. And, of course, their ultimate goal is to push for more research on the disorder.

Their efforts, and the community they have nurtured, also helped scientists to better define Lilly’s condition. “Different movement disorders have lots of similarities to each other and get classified based on the constellation of characteristics that people have,” says Ali Torkamani, the scientist from the IDIOM team who has worked most closely with the Grossmans. “But you need a set of patients that share these characteristics to form that diagnostic class in the first place.”

This was especially important for ADCY5 mutations, which produce symptoms that vary considerably in their nature and severity (Lilly sits at the more severe end). Without a large set of patients, it’s easy to get distracted by symptoms that are obvious in one or two people, but aren’t diagnostic of the disease as a whole.

Raskind fell into this trap. Based on her original German family, she considered myokymia—quivering, rippling muscle movements—to be a defining feature of their syndrome. It’s not, and she only recently realized that she’d been ignoring another family with ADCY5 mutations because they didn’t show this trait.

Once Torkamani and Raskind started identifying more people with ADCY5 mutations, they could finally gauge the full breadth of symptoms caused by those faults. And they have used that knowledge to find even more cases: There are now more than 50, about 10 of which have the same mutation as Lilly. The team will soon detail a newly defined set of defining criteria in the journal Neurology, with the hope that patients can be diagnosed based on symptoms alone, without needing a genetic test.  

This makes Lilly’s condition, now rebranded as ADCY5-related dyskinesia, very different from other genetic disorders, like Huntington’s disease or cystic fibrosis. In those cases, scientists toiled for years to find the genes behind well-characterized and diagnosable conditions.

“It was done in an almost haphazard way, but this is something we can expect to see more of,” says Torkamani. “You’ll see people get an initial diagnosis based on genome sequencing. Then, the patients themselves proactively establish a network and identify additional individuals with the same mutations. If it wasn’t for [the Grossmans] and their willingness to take this beyond just a diagnosis, to get the word out and identify new subjects, I don’t think we would have been nearly as successful as we have been.”

But what happens after diagnosis? Once you know the gene responsible for a new disorder, what then? Topol says that studies like IDIOM will eventually lead to three possible outcomes. In the best of these, a genetic diagnosis suggests treatments that lead to an outright cure (as in the now-famous case of Nicholas Vollker). Few cases will be corrected so easily, even with a new suite of powerful genome-editing technologies. “That category is going to be rare for a long time,” says Topol.

In the worst scenario, families still won’t get a diagnosis despite having their genomes deciphered. That’s the case for around 40 percent of families who have taken part in the IDIOM study so far, and there are many reasons for that. Their disorder might not be a genetic disease at all. The scientists might get a long list of candidate genes that are impossible to narrow down. The genes in question may rest in parts of the genome that are poorly characterized. “But those cases will fill in over time,” says Topol. “The sequence data won’t go away and it will get colored in by hundreds and thousands of other sequences.”

Lilly exemplifies the third and most likely scenario, in which genome sequencing hints at ways of controlling symptoms but provides neither cures nor easy solutions. Lilly, for example, started improving after taking Diamox but the drug’s effects soon wore off. When I spoke to the Grossmans in March 2013, the tremors had returned, albeit less severely than before.

Her doctors tried her on a variety of other possible drugs, to varying effect, but in the summer of 2014, Lilly was back to days of continual sleeplessness. Delirious with exhaustion and worry, the Grossmans checked her into hospital, where their doctor, Jennifer Friedman from the University of California, San Diego, prescribed her Valium. That night, she slept for four hours. “The nurse came in and apologized saying my night must be horrible,” Gay recalls. “And I was like: You have no idea! Four hours is heaven!”

On Valium, Lilly started sleeping again, but relapsed in January 2015 due to the stress of applying for colleges. Friedman prescribed another drug called Xenazine and her symptoms once again abated—just in time for Gay and Steve to take her to Europe for spring break. She soaked in the impressionist collections of Paris and bought a prom dress in London.

This seems like great news, but note that Lilly’s medical care hasn’t been directly informed by the results of her sequencing. In an ideal world, doctors would understand all the ways in which ADCY5 acts upon the body, and why various mutations send it astray. They could then choose drugs that target critical points in those pathways. But often, our knowledge of biology is far too incomplete to make such choices.

Friedman chose neither Valium nor Xenazine with ADCY5 in mind. “They were really chosen based more on her symptoms and because they had been effective in other children with ADCY5 mutations,” she says. “The sequencing was useful in terms of getting hints from other patients, but we still don’t really understand enough to make clear predictions about which medications work. We find the gene and there’s great hoopla and excitement, but we get stuck all the time. I don’t want to discount the power of knowing that information, but it’s really just the beginning.”

Gay and Steve Grossman, more than anyone, know that. They didn’t expect sequencing to offer them a quick fix, and they know that it will take a lot of research to approach anything resembling a cure. As they have repeatedly told me: It’s a marathon, not a sprint. But it’s also a marathon made considerably easier by having the certainty of a diagnosis, knowing that their daughter has a future, and being able to reassure other families who are going through the same ordeal.

Typically, the children they meet are much younger than Lilly. “The best feeling is seeing these tiny little kids and thinking: They’re not going to have to go through all this,” says Gay. “These mothers and fathers are young, and they have 2-year-olds. We’re 16 years ahead. They’re not going to have to go through nerve biopsies and muscle biopsies and MRIs and all these things we put Lilly through.”

She adds, “When we were Skyping with this girl in Australia, Lilly was saying: Mom she looks like me. Just the movements she made and the way she held her body. And I remember the hope that mum and girl had seeing Lilly as 18. They’re grateful to have found someone else.”