Researchers from the Icahn School of Medicine at Mount Sinai and Sage Bionetworks reported data from the largest genome study to date of a systematic search among hundreds of Mendelian disorders in hundreds of thousands of people not afflicted with any of these disorders in order to identify possible disease protective factors. The analysis report is published in Nature Biotechnology

The retrospective study is the first step of the Resilience Project, which was launched with the vision of identifying “rare individuals who are unaffected by genetic variants that should induce disease.” Genome analysis of these resilient individuals could help reveal naturally occurring, protective mechanisms that could serve as novel treatments for those afflicted by these diseases. 

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The research team analyzed DNA from 12 prior data sets, using a new targeted sequencing panel to screen 874 genes in 589,306 genomes for 584 genetic diseases. The diseases were mostly metabolic conditions, neurologic diseases, or developmental disorders with an onset in childhood accompanied by severe symptoms. All the genomes were from adults who were never diagnosed with any of these diseases; 13 healthy adults harboring the genetic variants associated with 8 diseases were identified through the analysis.

A significant challenge was that none of the final 13 candidates could be contacted with follow-up questions due to limitations in the informed consent policies from the original studies. Researchers hope to conduct a prospective study that will include a “more broadly useful consent policy.” Study findings support expanding genetic studies to systematically search for healthy individuals who are “buffering the effects of rare, highly penetrant, deletrious mutations.” 

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