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Apparently Healthy Carriers of Mendelian Mutations Detected by Resilience Project Pilot Study

NEW YORK (GenomeWeb) – A proof-of-principle study published online today in Nature Biotechnology suggests it is possible to profile very large groups of people to find individuals carrying Mendelian disease gene mutations that do not manifest in disease.

As part of a pilot study for the ongoing Resilience Project, researchers at Mount Sinai's Icahn Institute for Genomics and Multiscale Biology, Sage Bionetworks, and collaborators in the US, Canada, and China brought together targeted sequencing or genotyping data for nearly 900 genes in 589,306 individuals from a dozen large cohorts — including 23andMe customers who consented to participate in research, individuals from several medical studies, and participants in 1,000 Genomes and UK10K projects.

Though all of the participants were reportedly disease-free, the team identified 13 adult individuals with mutations associated with eight serious Mendelian conditions known to begin in childhood, from metabolic or developmental syndromes to cystic fibrosis. The results point to the possibility of incomplete penetrance for some Mendelian diseases, suggesting studies of unaffected mutation carriers might help in unearthing mechanisms that protect against disease.

"Some of those will be changes in other parts of the genome, some of them may be environmental, but finding those individuals is a starting point to searching for the other changes, for example in the genome, that might give us clues to develop therapies," co-senior author Stephen Friend, a researcher affiliated with Sage Bionetworks and Icahn School of Medicine, told reporters during a press briefing call last week.

The current retrospective pilot study was meant to examine the feasibility of using genomic data from healthy individuals to search for those who had managed to avoid disease, Friend further explained.

For their analysis, the researchers drew on data generated by teams on several continents: including data for more than 518,700 individuals with whole-genome genotyping (nearly 400,000 of which were genotyped for 23andMe alone), exome sequences for nearly 67,100 individuals, and in excess of 3,500 whole-genome sequences.

To do this, the team put together two sets of variants with ties to Mendelian disease, a core allele panel, made up of 674 well-annotated disease mutations in 162 genes involved in serious, early-onset conditions, and an expanded allele panel that included tens of thousands of variants strongly suspected of contributing to severe conditions that usually manifest themselves in childhood.

When they set the available genomic data alongside some or all of the variants in the disease-related allele panels, the researchers initially narrowed in on around 16,000 individuals who were suspected of being particularly resilient to disease due to the presence of 300 different genetic changes in their genomes, affecting 188 genes implicated in 163 diseases.

After using additional bioinformatics, filtering, and Sanger sequencing to toss out samples with inaccurate or low-confidence variant calls, the team was left with just 13 lucky individuals who had apparently dodged disease despite carrying serious mutations in genes involved in eight diseases.

"If you want to develop therapies for prevention, if you want to come up with ways of not just finding the cause, but ways of preventing the manifestations of disease, we now have tools that allow us to search for people who should have gotten sick among normal individuals," Friend said.

He and his co-authors cautioned that it is impossible to rule out the presence of unreported symptoms related to the mutations detected, since the type of consent obtained in the original studies didn't allow for participant identification or second contact.

With that in mind, the team is getting ready to kick off a prospective arm of the Resilience Project, which will include a web site for individuals interested in signing up to have their DNA profiled for similar analyses. The effort will be centered at the Icahn School of Medicine, though the team is also interested in collaborating with other groups to increase the scale of the analysis.

"Since the retrospective study was done by engaging many, our hope on the prospective study is similarly to have a core effort that is poised to go on at the Icahn School of Medicine. But any other group that has an interest in doing that would be most welcome," Friend said. "If the consent is set up in such a way that that individual is realizing that we would like to look at genes for resilience and there is the consent that says not just 'able to share' but 'want to re-contact,' I think that a distributed process of looking forward or going forward is the only way to go."

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