Enthusiasm for precision medicine, from the White House down to everyday physicians, is at a record high. But serious problems with the databases used to interpret patients’ genetic profiles can lead to “inappropriate treatment’’ with “devastating consequences,’’ Mayo Clinic researchers warned on Monday.
Their report describes the cases of some two dozen people who were told they had a potentially fatal illness and one who had a heart defibrillator implanted but, it turns out, never needed it. The individuals were family members who underwent genetic testing after a young relative died of a heart syndrome. Test results indicated they carried a mutation in a heart-related gene — and the database that the testing company used indicated it caused a serious disorder.
A reanalysis by Dr. Michael Ackerman, a genetic cardiologist at the Mayo Clinic, and colleagues with a more modern genetic database indicated the mutation was harmless, and invasive treatment unnecessary.
“This is the proverbial dark side of genetic testing and precision medicine,’’ Ackerman said. Because databases that companies use to interpret DNA tests are riddled with errors, “we’re starting to see a lot of fumbles,’’ with patients told a DNA misspelling is disease-causing when it isn’t.
Other experts are raising concerns about databases, too.
“It’s not a new problem,’’ said Michael Watson, executive director of the American College of Medical Genetics and Genomics. Until recently, he said, most genetics research focused on the United States and Western Europe, producing data that might not apply to other populations. A DNA variant that might cause disease in one ethnic group might not do so in others. That raises the concern some people treated with “precision’’ approaches will get useless or even harmful treatment.
The Mayo Clinic case began when a 13-year-old died in his sleep five years ago. Concerned that the boy had an undiagnosed heart condition, the family physician ran standard EKG and other heart tests on the boy’s brother and parents. When the brother’s EKG showed a short-lived glitch in his heartbeat, the doctor decided he had an inherited heart condition called long QT syndrome, which causes chaotic and sometimes fatal heartbeats, and implanted a cardioverter defibrillator, a pacemaker-like device that monitors heart rate and delivers a shock if it detects an abnormality.
The doctor also recommended that the brother and parents get genetic testing. That turned up a mutation linked to long QT syndrome, seeming to confirm the EKG. Dozens of relatives were scared into genetic testing, too. Eventually, some two dozen were found to have the long QT mutation.
It seemed like the perfect opening for precision medicine. Just as women with mutations in their BRCA gene can choose to have their breasts removed prophylactically, rather than wait for cancer to develop, so people with a mutation that causes long QT can have an ICD implanted. The boy’s brother got the implant.
There was something odd about the diagnosis of long QT, however. Neither the parents nor distant relatives had any symptoms, and the brother’s anomalous EKG event never recurred.
Ackerman was skeptical: Some 40 percent of patients at Mayo with a genetic diagnosis of long QT turn out not to have it. EKGs confirmed none of the relatives had the disorder, the Mayo team reported.
Ackerman discovered, from an old blood sample, that the boy who died did not have a mutation for long QT. If the family physician had ordered post-mortem genetic testing, the family would probably never have fallen into the black hole of genetic testing and overtreatment, Mayo physicians said.
Sharon Begley can be reached at sharon.begley@statnews.com.
