These 13 adults escaped deadly genetic childhood disorders, but how?

Scientists have identified 13 so-called “superheroes” — adults with disease-causing mutations who are mysteriously healthy — from a genetic survey of half a million people. Their resilience could hold clues to treating severe conditions like cystic fibrosis, but due to a technicality, they can’t be fully studied. The findings were published today in the journal Nature Biotechnology.

“Millions of years of evolution have produced far more protective mechanisms than we currently understand,” genomicist and study co-author Eric Schadt of the Icahn School of Medicine at Mount Sinai in New York City said in a statement. “Characterizing the intricacies of our genomes will ultimately reveal elements that could promote health in ways we haven’t even imagined.”

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Schadt is the co-founder of The Resilience Project, an international investigation into the hidden factors that prevent illness — the investigation that identified this panel of 13. Genetic resilience isn’t a new idea. Mutations in the CCR5 gene can ward off HIV, forming the basis of the therapy made famous by “the Berlin patient.” Other genetic alterations can boost hemogloblin levels to delay the onset or prevent sickle cell disease. However, healthy people aren’t typically surveyed for resilience mutations.

To reverse this trend, Schadt and his colleagues acquired 12 large genomic datasets that had been previously collected by other research projects. These data hives contained the sequenced genomes of 589,000 healthy people.

The researchers focused on Mendelian disorders — a broad-sweeping class of conditions caused by a mutation at a single point in a person’s genetic code. These disorders are rare, but often devastating during childhood, and include heavy-hitters like cystic fibrosis, sickle-cell anemia and Tay Sachs disease.

The team developed a method to sweep these genomic databases in order to spot mutations in 874 genes linked to 584 distinct genetic diseases. The screen identified 15,500 candidates with resilience. However, the team had to exclude swaths of this initial group for various reasons. For example, some mutations weren’t rare enough, meaning they occurred in more than 0.5 percent of the general population.

The scientists whittled this hoard of thousands down to 303 strong candidates. Following a review of available medical histories, the team felt confident that 13 people had survived to adulthood despite carrying what should have been debilitating mutations. The mutations among these superheroes have been linked to eight severe Mendelian diseases: cystic fibrosis, Smith–Lemli–Opitz syndrome, familial dysautonomia, epidermolysis bullosa simplex, Pfeiffer syndrome, autoimmune polyendocrinopathy syndrome, acampomelic campomelic dysplasia and atelosteogenesis.

However, none of these final 13 candidates can be contacted for future analysis, due to the informed consent policies mandated by the original studies.

“There’s an important lesson here for genome scientists around the world,” study co-author and genomicist Stephen Friend of the Icahn School of Medicine at Mount Sinai in New York City said in a statement. “The value of any project becomes exponentially greater when informed consent policies allow other scientists to reach out to the original study participants. If we could contact these 13 people, we might be even closer to finding natural protections against disease.”

Despite the study’s broad scope, the inability to directly follow up with these subjects significantly limits what can be concluded.

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“Reconnecting with these individuals would be important to verify that none had symptoms that could be linked to their genetic background. As such, some of the patients may have had the disease that went unreported,” geneticist Scott Hebbring of the University of Wisconsin, Madison, who wasn’t involved in the research, told GENeS. “In reality, most diseases can be expressed very differently between individuals, even in those who have the same genetic variant.”

Plus, genetic sequencing isn’t always accurate. It’s possible that the recorded genomes in the 12 datasets had typos, which could only be confirmed by direct analysis of the subjects’ DNA. At the moment, The Resilience Project only has access to the physical DNA from five of the lucky 13.

Without this DNA and direct follow-ups to rule out alternative explanations, ”the resilience of these individuals cannot be conclusively confirmed,” Emory University geneticist Patricia Page told GENeS.

In an editorial, Massachusetts General Hospital geneticist Daniel MacArthur points out that even with complete medical access, 13 people isn’t enough to conduct a comprehensive study on resilience.

“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. Achieving this goal will require incredibly large sample sizes,” MacArthur writes. “Finding genetic superheroes will require other kinds of heroism—a willingness of participants to donate their genomic and clinical data, and a commitment by researchers and regulators to overcome the daunting obstacles to data sharing on a global scale.”