SEATTLE -- A new analysis of genetic data from nearly 600,000 people has detected a tiny subset of disease-resistant "superheroes," individuals who have mutations that should have caused devastating disease -- but didn't, a Seattle scientist reported Monday.
Dr. Stephen Friend, president of Seattle's Sage Bionetworks, and his colleagues at the Icahn School of Medicine at Mount Sinai in New York, sifted through a massive data set pooled from a dozen previous genetic studies.
Of the more than a half-million people included in the analysis, 13 were found who survived to adulthood despite having genetic alterations that typically cause any of eight serious childhood diseases.
No one knows why they remained healthy, Friend said. But such people could one day provide insight into ways to prevent or treat such catastrophic disorders.
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"Instead of looking at people with disease, you need to look at people who should have gotten sick," said Friend.
He has worked for years on similar efforts through The Resilience Project, which tries to find healthy people with markers for fatal diseases, including dementias.
The current study, published Monday in the journal Nature Biotechnology, underscores the need for better data acquisition, collection and sharing, Friend said.
The scientists were able to access genetic data from 12 previous studies through several sources, including 23andMe, a private genomics and biotechnology firm in Mountain View, Calif. They screened data from 589,306 people to search for those resistant to 584 Mendelian disorders, diseases that often begin in childhood and are typically caused by mutations in a single gene.
They looked at 874 genes for completely penetrant mutations, meaning anyone who has them will invariably develop the disease. They originally identified about 15,000 possible candidates, but after careful review, the number shrank to just 13, Friend said.
However, because proper consent forms weren't on file, they could not contact the disease-resistant people for further information.
"It's this real feeling of being both terribly excited and really frustrated," Friend said.
Even more frustrating, those 13 people may have no idea they've dodged a genetic bullet. They're likely unaware they have mutations that should have caused cystic fibrosis, a serious lung disorder or epidermolysis bullosa simplex, a severe blistering disease found in so-called "Butterfly Children," whose skin is said to be as fragile as the insect's wings. Or the resistant patients may have mild expression of the diseases, puzzling symptoms that may have stumped their doctors.
Other conditions included in the search were Smith-Lemli-Opitz syndrome, a developmental disorder; familial dysautonomia, which affects nerve cells; Pfeiffer syndrome, which causes early fusion of skull bones; autoimmune polyendocrinopathy syndrome, an autoimmune disorder; acampomelic campomelic dysplasia, a skeletal malformation problem; and atelosteogenesis, another bone disorder.
All of the conditions can be devastating; some are fatal.
The results of the study are both compelling and daunting, wrote Daniel McArthur, co-director of medical and population genetics at the Broad Institute of Harvard and MIT, in an accompanying editorial. The massive analysis yielded only 13 people who were resistant, and no more than three each for any disease variant, he noted.
"This suggests that even with a million properly consented and deeply sequenced samples, it is extremely unlikely that enough genetic superheroes will be detected to enable a statistically well-powered genome-wide search for the genetic variants that modify disease genes," he wrote.
Scientists have known for years that some people with genetic mutations that typically cause disease can remain unaffected or have a milder form of the disease. There are people with cystic fibrosis who don't develop severe lung disease, for instance, or women with BRCA-positive genes who don't develop breast cancer.
Friend said he and his colleagues were careful to look only for mutations regarded as completely penetrant, so that those who were resilient were extreme outliers.
There are several possible explanations for why such individuals might not be affected, issues that will require further study, noted Dr. Michael Bamshad, a professor of pediatrics and an expert in medical genetics at the University of Washington, who was not involved in the study.
"More importantly, we will need to identify many, many more such 'resilient' individuals who are willing to openly share their health and genetic data in order to identify what protects them against disease," Bamshad said in an email.
Friend and his colleagues agree. To that end, they are collecting data from healthy volunteers who agree to share their genetic information. People interested in signing up can visit The Resilience Project website at resilienceproject.com.
"This project could never have been done without people willing to share data," Friend said.