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Discovery of healthy people carrying severe disease-causing mutations

Nature Biotechnology


A genomic analysis of more than half a million people reveals 13 individuals who appear to remain healthy despite carrying genetic mutations linked to severe childhood diseases. The findings are reported online in Nature Biotechnology this week. Although the biological reasons for this resilience are not yet understood, the study provides a first step towards pinpointing genetic variants that may protect against such diseases and highlights the need to re-evaluate previous assumptions about the causal link between genetic mutations and some severe diseases.

Mendelian disorders, such as cystic fibrosis, can begin early in childhood and are generally caused by mutations in just one gene. These mutations are assumed to be completely penetrant - any individuals who carry the mutations will inevitably develop the associated disease symptoms. However, genetic testing has been largely limited to people who exhibited disease symptoms and their families, opening up the possibility that these mutations may have gone unnoticed in a small number of healthy people.

Stephen Friend, Eric Schadt, Rong Chen and colleagues used genetic data from 589,306 individuals to look for candidates resilient to 584 severe Mendelian childhood disorders. They searched 874 genes for completely penetrant disease-causing mutations, which were verified by a team of board-certified clinical geneticists, medical consultants, bioinformaticians, and genetic counselors. This expert panel also screened available health information to ensure that none of the individuals deemed to be healthy reported any subtle associated disease symptoms.

Their analysis uncovered 13 individuals who appeared to be completely resilient to one of eight Mendelian childhood conditions. The authors suggest that these individuals may hold the key to identifying factors that mediate the effects of highly penetrant disease-causing mutations and could aid in the development of much-needed targeted therapies. However, they note this will require the identification and analysis of many more resilient individuals, which itself will depend on the analysis of many millions of genomes.

In an accompanying News & Views article, Daniel MacArthur writes that “the researchers could not recontact the majority of resilient individuals for further study because of a lack of necessary consent forms…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.”

doi: 10.1038/nbt.3514 | Original article

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