A lot can be learned from the exception to the rule. As reported in the April 11 Nature Biotechnology, researchers scrutinized data from more than half a million genomes to identify 13 healthy adults who harbor mutations that normally cause deadly or debilitating childhood diseases. That these lucky few escaped any clinical manifestation of those diseases suggests that they carry other mutations that protect them. Such beneficial variants might eventually lead to new treatments or cures, suggest the researchers, led by Stephen Friend at Sage Bionetworks, Seattle, and Eric Schadt at the Icahn School of Medicine at Mount Sinai, New York. The researchers are already planning to find genetic variants that protect people from diseases of aging, such as Alzheimer’s. The story made the pages of The New York Times.

Others were intrigued, but some cautioned that the strategy may work less well for neurodegeneration. “This is a really exciting approach to find individuals who escape [disease], but because people with neurodegenerative diseases live a long time, protection will be less black-and-white than that preventing lethal childhood disease,” noted Rosa Rademakers, Mayo Clinic, Jacksonville, Florida. Alison Goate, a geneticist at Mount Sinai who did not work on this project, agreed. “It is fantastic to see that it actually worked,” she said, but noted that many neurodegenerative diseases are not fully penetrant in the way these childhood diseases are. Nevertheless, she thought that familial AD caused by mutation in APP or presenilins might be similarly amenable to this approach. Co-author Jason Bobe at Icahn was optimistic about that idea, telling Alzforum that even if one person with a familial AD mutation had a much later disease onset, it could be enough to find the “smoking air bag.” In fact, working with Randall Bateman and colleagues at Washington University, St. Louis, Bobe and colleagues have already identified one such person in the DIAN familial AD cohort. Now in his late 60s, Doug Whitney, from Port Orchard, Washington, harbors an autosomal-dominant AD mutation, but remains disease-free. The mutation killed 11 of his close relatives, most by their mid-50s.

Resilience Project
Though extremely large, the childhood resilience project was really a feasibility study, according to Friend. Over many decades, an enormous amount of work went into genetic studies to find causes of diseases. This has not always led to treatments, so Friend decided to change tack. “Our work was based on the idea that if you wanted to find clues to prevention, you should look at healthy individuals who should have gotten sick,” he said. To this end, joint first authors Rong Chen and Lisong Shi at Icahn screened 874 gene sequences among 589,306 genomes of healthy adults for mutations known to cause severe childhood illnesses. Collaboration and data sharing were key for the project. 23andMe of Mountain View, California, supplied almost 400,000 sequences; the remaining 190,000 came from 11 current or past genetics studies, public and private, in North America, China, the United Kingdom, Finland, and Sweden.

To avoid ambiguity, the researchers focused on mutations that cause fully penetrant Mendelian disorders—in other words, diseases caused by a single mutation. Mutations in the 874 genes screened have been linked to 584 unique disorders spanning 17 disease categories, with metabolic, neurologic, and developmental conditions most represented. From nearly 16,000 healthy candidates identified as potentially resilient to these mutations, Chen and colleagues excluded all but 303 because of ambiguities in the genotyping or because individual data were unavailable for further review. The researchers whittled that number down to 13 based on a rigorous review of medical and genetic data.  

Of the 13, three people carried mutations in the CFTR gene that cause cystic fibrosis. Three dodged atelosteogenesis, which manifests as severe skeletal deformities and is caused by mutation in a sulfate transporter; two had 7-dehydrocholesterol reductase mutations that cause Smith-Lemli-Opitz syndrome, a severe developmental disorder due to lack of cholesterol. The other five people had mutations in different genes that normally cause skeletal, autoimmune, dermatologic, and neurologic conditions.

Why did these people escape a devastating disease? The scientists call the work to address this question “decoding.” They borrow the concept of the decoding board from oncology, where panels of experts of various disciplines brainstorm how to treat a particular tumor. “Decoding here is the reverse,” said Bobe, “we are trying to find out why the person does not have an illness by considering a variety of potential protective factors.”

Here the researchers ran into a snag. None of the 13 individuals had consented to be re-contacted when they agreed to donate their DNA. “This was a real hindrance,” said Friend. He likened it to taking the wrapping off a gift, but not being able to open the box.

This will not be an issue in prospective studies, for example in the DIAN cohort. Bobe would not reveal details of that study, save to say it was in planning. The researchers are also planning a larger prospective study that will invite anyone who thinks they may be resilient to a disease to sign up.

Could this work pay off for other neurodegenerative diseases? In theory, yes. Goate’s strategy is to study people who remain cognitively normal into old age yet carry the ApoE4 allele, a relatively common risk factor for AD. Even for rare variants the approach might work. Both Goate and Rademakers noted that a search of the Exome Aggregation Consortium (ExAC) database suggests there are people with presenilin and progranulin mutations who do not or will not have dementia. “We found about 30 people with loss-of-function granulin mutations in the ExAC database, but there is no way they could all develop frontotemporal dementia, because then the prevalence of the disease would be much higher than it is,” said Rademakers. She collaborates with other researchers around the world to find genetic variants that modify age of onset of FTD caused by granulin mutations. “Another approach would be to study unaffected carriers, but sometimes they will be difficult to find because the disease is so rare,” said Rademakers. The Nature Biotechnology paper illustrates the difficulty, since Chen and colleagues found so few people from such a large screen.

Nevertheless, Whitney proves that it can happen. The question now is whether the researchers can find the protective factors in his genome. If there is a truly strong biological candidate, then it may be possible, said Rademakers, but she also cautioned that when looking for more subtle modifiers of age of onset, researchers may need to find more than one or two resilient people carrying the same mutation for the study to be informative.

Historically, even a single exception to the rule can sometimes be sufficient. Stephen Crohn, who was famously resistant to HIV infection, turned out to have a mutation in CCR5, a surface receptor the virus latches on to before it infects white blood cells. CCR5 antagonists are now used to treat HIV AIDS.—Tom Fagan


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External Citations

  1. The New York Times

Further Reading


  1. . Translational genomics. Clues from the resilient. Science. 2014 May 30;344(6187):970-2. PubMed.

Primary Papers

  1. . Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases. Nat Biotechnol. 2016 Apr 11; PubMed.