They are the genetic equivalent of unicorns: 13 adults with genes for rare disorders that always strike in childhood, yet who never developed the disease. The genes are not for complex diseases, such as cancer where DNA variants merely raise the risk of developing a disease; these mutations cause the disease — cystic fibrosis or familial dysautonomia, for example — as surely as 22 makes you go bust in blackjack. Or so everyone thought.
But a new study, published Monday in Nature Biotechnology, challenges that notion. Researchers searched genetic data from nearly 600,000 people in scientific studies or databases of DNA testing company 23andMe, looking for mutations in any of 874 genes known to cause one of 584 severe childhood disorders. The scientists identified 13 people with a mutation that should have made them very, very sick — or dead. Yet here they were, healthy adults.
The mutations cause so-called Mendelian disorders, in which a single mutation is all it takes: carry the mutation, get the disease. If the 13 exceptions really managed to buck this rule, it could upend the way scientists seek treatments for genetic diseases.
“If you want to find clues to prevention or treatment … you want to look at people who should have gotten sick” but didn’t, Stephen Friend, president of Sage Bionetworks and a co-leader of the study, told reporters.
That’s the polar opposite of the prevailing approach, which targets (and attempts to reverse) the genes’ disease-causing effects. That strategy has largely failed. Few drugs have been developed for Mendelian disorders, mostly because it’s extremely difficult to replace a broken gene with a drug; gene therapy, too, has largely disappointed.
But learning how nature keeps people healthy when their genes are broken might lead to cures or prevention, say proponents of the resilience approach: in 2014, for instance, Friend and Eric Schadt of the Icahn School of Medicine at Mount Sinai in New York City, co-leaders of the new study, launched the Resilience Project to find mutations that override disease-causing mutations.
The general idea of resilience genes isn’t crazy. For instance, a mutation that keeps babies from making adult hemoglobin also protects them from sickle cell disease, even if they have the gene for it, scientists reported last year.
Outside scientists gave the study mixed reviews. Dr. Eric Topol of Scripps Health called it “a standout contribution.” Genomics researcher Daniel MacArthur of Massachusetts General Hospital, who wrote an accompanying commentary, called it “an ambitious first step” but warned that “some of their resilient cases may be mirages.” He and several other scientists pointed out that because Friend’s team could not resequence the genomes of the 13 people whose mutations should have caused Mendelian diseases they could not confirm the presence of disease mutations; DNA sequencing, notoriously inaccurate, always needs to be checked multiple times.
An alternative explanation for the finding is that the 13 are genetic mosaics, in whom different cells have different genotypes. That can happen in rare cases when two early embryos fuse. If so, then cheek cells sent to 23andMe, for instance, might have cystic fibrosis mutations, while lung cells didn’t, explaining why they did not develop CF; no “resilience” genes needed.
The study couldn’t actually identify resilience genes because, for most of the individuals, full genome sequences aren’t available. 23andMe, for instance, tests for mutations at sites linked to diseases, a process called genotyping. Because customers and study volunteers did not consent to being recontacted or retested, the researchers hit a dead end.
Still, though identifying resilience genes will require additional studies of millions of genomes, the basic approach is promising.