Researchers are using exome sequencing—zeroing in on the genes that encode proteins—to explore the biology of certain diseases. But to use exome sequencing to diagnose disease, the technology needs to move to the clinic. HHMI scientists are beginning to bridge the laboratory and the clinic to use exome sequencing to help patients—most often, those with rare, hard-to-diagnose diseases.
At Brigham and Women’s Hospital in Boston, for example, HHMI investigator Christine Seidman uses exome sequencing to find the genes responsible for inherited forms of heart disease. One area she focuses on is cardiomyopathy, a progressive deterioration of the heart muscles. The condition is often undiagnosed until adulthood, when symptoms have progressed and can lead to heart failure.
When patients visit her clinic, Seidman’s first goal is to determine which variety of cardiomyopathy they have. One—called hypertrophic—is caused by mutations in one of eight genes, while a second type—dilated cardiomyopathy—can be caused by a mutation in one of 40 other genes. And new mutations are still being discovered. Seidman’s recent discovery of a gene called TTN was published February 16 in the New England Journal of Medicine. A mutation in TTN explains approximately 20 percent of cases of dilated cardiomyopathy.
It’s often impossible to tell which type of cardiomyopathy a patient has based on the symptoms, but this knowledge is vital for family members who may also be at risk. Interventions like pacemakers and more active monitoring of the disease are often required for the hypertrophic variety.
“With hypertrophic cardiomyopathy, sudden death can occur without prior warning symptoms,” says Seidman. “If you have family members at risk for inheriting a gene mutation that causes hypertrophic cardiomyopathy, you’d want to know, so proper interventions can be taken to prevent sudden death and other serious events.”
Analyzing the genes is the only way to identify each patient’s particular mutation—and hence the type of cardiomyopathy. This is where Seidman has turned to exome sequencing.
“You could either sequence the eight genes associated with hypertrophic cardiomyopathy and the 40 dilated cardiomyopathy genes, or you could just go ahead and sequence the exome,” she says. “It’s becoming increasingly cost-effective to sequence the exome. The additional information may provide insights into other genes that impact the clinical course of disease.”
For now, Seidman is using this technique only for research purposes; her next step is to take it to clinics as a diagnostic tool. She thinks this version of personalized medicine—to clarify diagnoses—will be available in the near future.
The Challenge: Devising Treatments for New Diagnoses
For other conditions, however, the use of exome sequencing to guide treatment plans and diagnosis is not as immediately obvious. And many call exome sequencing useless if it won’t change a doctor’s treatment plan. Interesting for research purposes—yes—but worthwhile for doctors trying to help patients? Not yet.
“We’re already past the point where just doing individual gene tests makes sense financially,” says HHMI investigator Todd Golub, who studies cancer genetics at the Dana-Farber Cancer Institute. “But the challenge is the need for drugs that match all these mutations we might find. In many cases there won’t be a drug on the shelf to match someone’s disease-causing mutation. So the important work over the next decade will be to discover those new drugs.”
For diseases that have doctors stumped as to a diagnosis, however, exome sequencing may offer help sooner, according to Richard Lifton, at Yale School of Medicine, who studies rare diseases.
“If you go to the neonatal intensive care unit of any big hospital around the country,” he says, “there will be patients who have had literally million-dollar workups, and have been seen by every specialist, and still have no diagnosis.” Using exome sequencing to diagnose those tiny patients, Lifton thinks, will reveal their disorders and perhaps even suggest treatments. Some patients will likely have rare presentations of common diseases, while others will turn out to have unheard of genetic syndromes.
At the University of California, San Diego, Joe Gleeson is already using exome sequencing to diagnose tough cases. In a recent paper in Science Translational Medicine, his group published the results of a study that used exome sequencing on patients from 118 families in which affected children displayed neurodevelopmental disorders that began with symptoms in infancy or early childhood but for which the children had not received a genetic diagnosis. Diagnosing such disorders is tricky—the same disease can present with drastically different symptoms in two patients, and diseases with different causes can appear similar.
“While these diseases are individually rare, they are very expensive to diagnose and treat and probably make up 10 percent of total health care costs,” says Gleeson.
In their recent work, Gleeson’s team gathered blood samples from participants. Each patient had an initial diagnosis, or at least a best guess as to what class of disease was present, but doctors were unsure of the diagnosis in all cases. All were from areas of the world—mostly the Middle East—with high rates of marriage between cousins, making the prevalence of inherited disorders high.
“Part of the reason we can use this technology so efficiently is that we’ve built up large cohorts of patients in these parts of the world,” says Gleeson.
When the scientists analyzed the exome sequences, they discovered 22 mutations in genes that have never before been linked to diseases. For example, one family with symptoms including microcephaly and diabetes had a mutation in a gene called EXOC8. Knowing that mutations in this gene can cause disease may now motivate scientists to study the gene further—it’s already known to be required for transporting materials from the inside of cells to the outside in a process called exocytosis.
In 10 other families, Gleeson and his team found mutations suggesting that the initial diagnoses were wrong. While the symptoms suggested they had one disorder, exome sequencing clarified that they instead had an unusual presentation of a different disorder. For example, one family initially diagnosed with a disease caused by inherited vitamin E deficiency was found to have hereditary spastic paraplegia. Brain MRIs confirmed the new diagnosis. The vitamin E therapy—which hadn’t helped their symptoms—has been halted. Another family, diagnosed with recessive intellectual disability—a broad diagnosis—was discovered to have a disease that falls into a different category, one linked with the way the body metabolizes nutrients. Their cells don’t properly metabolize certain amino acids. While there’s no cure for this disease, a plan to use dietary supplements to treat children with the disorder is in the works.
“What the sequencing is doing is improving patient diagnoses,” says Gleeson. “We lump together all these ill-defined conditions, but hiding in there is a whole range of unique and rare diseases, some of which will represent treatable conditions.”
Gleeson says that exome sequencing studies are leading to more synergy between the lab and the clinic. Every time a disease gene is identified, it can be used both for clinical testing and for motivating studies of the basic biology of that gene. It’s a boon, he says, for patients and researchers alike.--S.W.