In July 1998, Robert Stone was a healthy 13-month-old baby. Then, suddenly, he wasn't. He began having one-minute spells of muscle failure, such as abruptly dropping a toy or falling over. After a few days, that escalated into 10-minute episodes that affected muscles throughout his body. He spent weeks in the hospital until doctors ruled out everything they could test for and sent him home. By age 3, Robert was confined to a wheelchair and eating through a tube. He seemed to understand everything around him but was unable to speak. For 13 years, his parents, Roger and Jeneva Stone, spent thousands of dollars (even with insurance) taking him from one hospital to another, searching for a diagnosis. They carried a binder stuffed with reports from more than 100 diagnostic tests. Just four showed anything out of the ordinary, and no one knew how to interpret any of them.
Then, in the summer of 2011, Jeneva heard about the Rare Genomics Institute, at the time a nascent nonprofit that sought to raise money to pay for sequencing the genes of children with mysterious diseases. RGI creates online fundraising campaigns for each child using the crowd-funding model most associated with Kickstarter. Crowd-funding works through Web pages that describe specific projects in need of money and solicit online donations—typically small contributions from family, friends, and friends of friends.
RGI's founder, Jimmy Lin, Med '12 (MD/PhD), is a 33-year-old computational geneticist at Washington University in St. Louis. He had done research in Johns Hopkins oncologist Bert Vogelstein's lab, sequencing the genomes of cancer tissues, and worked clinical rotations at the Kennedy Krieger Institute. While at Kennedy Krieger one day in the spring of 2011, Lin met a family whose young son had a mysterious, painful illness. After several hours of tests, Lin heard his colleagues tell the boy's mother that they thought her son had a rare genetic disease, but they couldn't know for sure. "When I heard that, I was like, whoa, I spent my PhD sequencing genomes for cancer. Why don't we do this for rare diseases?" Lin recalls. He has not forgotten the look of disappointment on that mother's face. "I thought, there has to be something that we could do for families like this."
Some 7,000 rare diseases, most with genetic roots, affect 350 million people worldwide. Gene-specific tests have been developed for some rare diseases, such as cystic fibrosis. For the rest, the only hope of finding a diagnosis lies in sequencing the genome. The money needed to screen a handful of genes a few years ago can now pay for rapid sequencing of thousands of genes, but it costs several thousand dollars per person and is not usually covered by medical insurance.
Lin decided to bridge that gap and founded RGI. RGI first finds families whose children are most likely to benefit from gene sequencing. The children usually have clinical features that point to a genetic disease, such as anatomical defects, as well as a history of negative results on other kinds of genetic tests. For each child, RGI then creates a fundraising page on its website. Once a family raises the $7,500 minimum—enough to sequence the exome, or protein-coding part of the genome, of the child and both parents—RGI connects them to participating scientists who can read genomes and root out possible disease-causing mutations. Pinpointing a genetic cause can be a huge relief to families. But having a diagnosis also raises the possibility of finding treatments that have worked on others with similar diseases, or even developing new treatments.
In July 2012, RGI completed the sequencing of its first child—a 4-year-old with speech and developmental delays who carries a mutation that's almost certainly the cause. So far, 20 projects have launched; nine have been fully funded and three completed, Lin says. This kind of analysis is still in its infancy, and researchers often can't deduce which mutations are benign and which cause trouble. As luck would have it, the researchers have fingered genetic culprits in all three of the RGI children who have been sequenced so far. Basing his conclusions on published studies, Lin estimates that the overall success rate will be between 25 and 33 percent.
For the Stones, RGI was worth the risk. "I saw it as a last-ditch effort to figure out what was wrong," Jeneva Stone says. Within six weeks, the Stones' campaign had reached the $7,500 goal. Nine months later, they had Robert's results. He carries two mutations, each extremely rare, one on each copy of a gene called PRKRA. Errors in this gene cause a syndrome called dystonia 16; Robert is the ninth reported case.
Like many families, the Stones found solace in the certainty of the diagnosis. They won't be adding any more useless test results to their binder. The diagnosis also indicates that certain drugs are likely to work slightly better than others, and that Robert probably has a normal intelligence. The discovery also revealed that his disease will most likely get worse, but that also is useful to know. "We can prepare ourselves and our family, and also provide Robert with the appropriate types of emotional and life support," Stone says. "Information is a source of power."