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Scientists could learn a lot from 13 people whose genetic mutations should have made them sick, but didn't

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Their DNA could hold the secret to treating severe childhood diseases

James Bareham

Scientists have identified 13 people who carry genetic mutations that should cause severe diseases, but who are surprisingly healthy. Because of this, researchers think their DNA, or the environment in which they live, might hold keys to treating conditions that are currently thought of as untreatable.

These 13 people were never diagnosed

In the study, published today in Nature Biotechnology, researchers at Mount Sinai sifted through more than 589,000 genomes in search of people who are resistant to the effects of severe mutations, a characteristic that scientists refer to as "resilience." They identified 13 people who survived to adulthood despite displaying genetic mutations that are known to cause one of eight severe childhood diseases. Among the diseases were cystic fibrosis — a chronic lung disease that carries an average lifespan of 37 years — and Smith-Lemli-Opitz syndrome, a disease that causes malformations and behaviors resembling autism. But, for reasons unknown, these 13 individuals were never diagnosed.

In recent years, researchers have discovered a number of genetic variants that allow people to remain healthy, despite being at a high risk for disease. In 2006, for example, researchers announced that they had identified a young woman with surprisingly low levels of cholesterol in her blood. These low levels were the result of two mutations on a gene called PCSK9 — mutations that eliminated an important cholesterol-regulating protein. Since then, drug companies have studied the mutations to develop new cholesterol-lowering drugs. The knowledge that such "resistant" people exist inspired the researchers at Mount Sinai to perform a large genetic search to identify more of them. Instead of looking for ways to fix the effects of a disease-causing mutation, "we came up with the idea of trying to identify those individuals who have the mutations, but didn't manifest the disease," says Eric Schadt, a biologist at Icahn School of Medicine at Mount Sinai who co-authored the study. The long-term goal of the research would be to mimic whatever’s protecting those people in others who show symptoms. "However nature overcame that defect, that becomes your therapeutic," Schadt says.

The search for resilient individuals started with gathering a ton of data. Through various agreements, the researchers obtained medical and genetic information collected during 12 previous studies — including data gathered from the personal genomics company 23andMe — for a total of 589,306 genomes. Then, the scientists used computer programs to search for people who are resilient to serious conditions that manifest in childhood and that can be caused by a single mutation, or illnesses known as "childhood Mendelian diseases." By weeding out bad and incomplete data, the scientists identified 303 candidates that met their criteria. The group then parsed through their genome and medical files by hand. In the process, researchers found that some candidates had actually been misdiagnosed with other diseases.

Their illnesses "would have been impossible to miss"

Eventually the scientists settled on 13 adults whose illnesses "would have been impossible to miss," Schadt says. All carried severe mutations for at least one of the following illnesses: cystic fibrosis, atelosteogenesis, familial dysautonomia, epidermolysis bullosa simplex, Pfeiffer syndrome, autoimmune polyendocrinopathy syndrome, acampomelic campomelic dysplasia, and Smith-Lemli-Opitz syndrome. Schadt admits that 13 people is not a large enough number to determine what’s allowing each of them to remain healthy, but it’s an important starting point.

The study is "sort of a wonderful reversal of the way we’ve been looking at Mendelian disease for the past 30 years," says Dietrich Stephan, a human geneticist at the University of Pittsburgh who wasn’t involved in the project. The researchers "went through this whole triage process to ensure that these people had mutations for really nasty diseases that are obvious in adulthood, and they built a very convincing case that says that if these people had these diseases, we would know about it." Because of this, the study introduced the notion that there are other drug targets besides the disease-causing mutations that scientists could use to treat people who are sick, he says.

Not everyone was impressed by the findings. Andrew Wilkie, a geneticist at the University of Oxford who studies Pfeiffer syndrome, says that scientists have already documented cases where, despite having the mutation mentioned in the study, some members of the same family never develop symptoms. That means that the Pfeiffer syndrome mutation doesn’t meet the researchers’ requirement for a genetic variant that unambiguously causes a disease, he says. "The implications [for Pfeiffer syndrome] are quite clearly over-hyped," he says.

In response, Schadt told The Verge that his team was aware of the case Wilkie mentioned. He also thinks the example is a "good demonstration" of why this type of search for resilient individuals is justified. For him, it highlights "the search strategy we advocate in the paper, to search for resilient individuals in extended families with individuals that have the disease," he says.

"I am a bit surprised it got into Nature Biotechnology!"

But that’s not the only problem with the study, Wilkie says. One of the biggest limitations is that the researchers couldn’t verify their own findings by contacting the 13 individuals. The reason for that has to do with the consent forms that each participant signed when their DNA was collected. All consented to sharing their data with other research groups, but many had not given permission to be recontacted by those researchers. That means that there’s no way to corroborate the scientists’ conclusions, Wilkie says. "Sorry not to be more enthusiastic about this work; I am a bit surprised it got into Nature Biotechnology!"

David Cutler, a population geneticist at Emory University, also questions the importance of the findings. The study essentially points out that the disease risk associated with some of the mutations isn’t as high as scientists thought, and that isn’t surprising at all, he says. The original evidence supporting that each of these mutations always causes a disease was "so weak" that it would "almost be improbable" that the authors couldn't find evidence to the contrary, he says. "It is a nice little paper, but perhaps more trivial than it sounds."

The scientists will launch a ResearchKit study this year

Schadt knows the study has its limitations. He worries, for example, that someone may have sent their sick child’s DNA to 23andMe under their own name, likely for privacy concerns. If that happened, it would explain why someone would appear to have reached adulthood without becoming ill, he says. It’s also possible that someone may be a genetic "mosaic" — a term used to designate people who, by a genetic quirk, have different genetic information in different parts of their body. If that were the case, it’s possible that someone’s blood sample contained the mutation while the part of their body that should be affected by the resulting disease does not. But for Schadt, the take-home message of the study isn’t that people who are resilient to these diseases exist. The real revelation is that finding resilient individuals by looking at healthy people is possible — and it should be done again, he says.

To that end, the Mount Sinai researchers will be launching a new genetic study this year. This time, the researchers will gather their own data using, in part, an app created using Apple’s ResearchKit, a software platform that aims to help researchers recruit iOS users to participate in studies. People will be able to sign up for the study through the app and even electronically consent to having their DNA collected; the researchers hope to enroll one million people, Schadt says. And this time, the consent process will include a clause about recontacting folks who might be resilient to severe childhood mutations. "It’s a positive thing; your genome could hold the secret to a treatment for others," Schadt says.