When most people’s kids have trouble with their teeth, they consult a dentist. When geneticist Heidi Rehm’s daughter had a problem, Rehm decided to get part of her daughter’s genome sequenced.
Rehm learned that the problem went well beyond her daughter’s teeth. Instead, she discovered that her daughter had a rare mutation that put her at risk of developing dilated cardiomyopathy, a disease than can lead to heart failure. The disease is often hereditary, so Rehm got her own genome sequenced, and discovered that she, too, had the same mutation, as did her mother. However, no one could tell Rehm what the genetic results meant: how likely was she to get the disease because she had this one mutation associated with it?
As a genetics expert—Rehm is the clinical director of the Laboratory for Molecular Medicine in Cambridge, Massachusetts—instead of letting the bad news paralyze her, she was motivated to find out more. She started by searching for people with the same mutation to ask how the disease has progressed for them. So far she’s identified a total of nine cases around the world—including herself, her mother, and her daughter.
That’s not much information, but it’s still more than another worried mother in Rehm’s position would have. When most patients get results like Rehm’s, they have no way to know what their genetics mean for their futures. Rehm wants to solve that problem.
Genetic sequencing is the predominant tool used in personalized—or precision—medicine, which monitors people’s DNA and biomarkers to improve their healthcare. Precision medicine allows doctors to alert healthy patients to their disease risks and match sick patients to effective treatment plans.
Precision medicine has led to many advances in healthcare. For example, a subset of leukemia patients have a genetic mutation that makes them respond positively to a certain drug, said David Steensma, an oncologist at the Dana-Farber Cancer Institute. If the oncologist knows to screen for that mutation, the patients can be cured. “I have patients [with the mutation] who had been resistant to several other treatments, but now are alive several years later when they wouldn’t have been,” Steensma said.
However, the connection between many genetic mutations and possible diseases remains poorly understood, as was the case with Rehm’s daughter, so different doctors may give patients very different information about their disease risks after looking at the same genetic data. Rehm is involved in several initiatives within the field of precision medicine to standardize and improve genetic research practices and doctor-patient discussions. She helped develop the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines for assessing the disease risk of genetic mutations using a five-tier system that ranges from pathogenic to benign. She’s also working on improving databases in which labs can share their interpretations of which mutations cause diseases.
Building a scientific consensus on which mutations have a high likelihood of causing disease is important because uncertainty can have serious consequences. Dr. Mary Norton, an obstetrician-gynecologist and professor at the University of California, San Francisco, is an expert in prenatal genetic testing and said that the testing often reveals mutations of unknown significance. “You might have to say, ‘We don’t really know. Maybe it’s really bad, maybe it’s nothing. Do you want to terminate your pregnancy?’” Norton said.
Geneticists including Norton stress the importance of patients receiving counseling about what the tests could reveal before getting their genomes sequenced. If not properly counseled beforehand, including about the possibility of uncertain results, some patients may find out information that they wish they could unlearn, Norton said. “Our ability to test has far outstripped our ability to interpret. It’s going to be complicated. We have to be mindful,” Norton said.
When labs interpret a mutation incorrectly, having a procedure in place to revisit the results or make the data public so outside geneticists can catch the error can make a big difference. However, many laboratories that sequence genomes lack detailed procedures for data sharing or reanalysis, according to a survey of current practices published in Nature co-authored by Rehm. Rehm wants all labs to “share and compare” their data results.
“From anecdotes, I knew [genetic interpretation] was being done with very different standards, and inaccurate information was being delivered to patients,” Rehm said. She helped create a system for labs that share their data to identify conflicting interpretations—cases where different labs looked at patients with the same mutations and reached different conclusions about their disease risk. “Now we have targeted efforts to systematically resolve these differences,” Rehm said.
When it comes to interpreting genetic results, “we’re very clumsy at this stuff right now,” said Dr. Michael Snyder, the director of the Stanford Center for Genomics and Personalized Medicine, “but in the future we’ll get good at it.”
Snyder has personal reason to believe in the utility of genetic sequencing: his lab has been monitoring his genome and other biomarkers for seven years. (He gets blood drawn up to 20 times a year.) Rehm calls him the “poster child of self-monitoring.” This testing helped him to discover he was at risk of developing type 2 diabetes shortly before he got the disease. Because the lab caught it early, Snyder has been able to keep his diabetes well managed.
Snyder said that as geneticists gather more data and figure out the significance of mutations, genetic sequencing will change how people think about healthcare. He envisions a future where everyone gets genomic and biomarker checkups. “We generally only see people when they get sick or ill. We rarely put much effort to keep them healthy,” Snyder said. Precision medicine could help people get treatment sooner or keep them from getting sick entirely. Along with catching Snyder’s diabetes, his lab has helped patients find cancer in very early stages, know which cancers to keep an eye out for, and understand how their bodies respond to different diet and exercise choices.
Rong Chen, the director of Clinical Genome Informatics at the Icahn School of Medicine at Mount Sinai, who has worked with Snyder before, said that with Snyder’s and others’ work “collecting this sort of longitudinal data, you’ll be able to change people’s lives.”
However, Chen is not quite as optimistic as Snyder about a bigger role for precision medicine in the near future. There are numerous roadblocks to developing a better knowledge base about how to interpret genetic data, Chen said, including lack of data sharing, issues with data quality, and gathering enough patients—especially from underrepresented populations.
Rehm mentioned another major roadblock: the possibility of bankrupting the healthcare system. “If we unleash genomes on everyone, and a good percentage of people have got things that need to get followed up, I don’t know that our healthcare system can afford to deal with that,” she said. In particular, until doctors know which genetic mutations actually are significant and high risk, the healthcare system would end up paying for a lot of unnecessary follow up.
Yet Rehm is determined to follow up on her family’s rare mutation. She still doesn’t know if it means they will one day get the disease. She says she doesn’t let the finding get to her. “Should I be worried about it? No. Because I can’t change it,” Rehm said. But she continues to track down any information that she can. “Why? Because I want to know what’s in store potentially for me, my daughter, and my mother.”