NATURE BIOTECHNOLOGY VOLUME 34 NUMBER 5 MAY 2016 531 ARTICLES Advances in genomic technologies have rapidly expanded our knowledge of the genetic basis of human disease. To date, >6,000 Mendelian disorders have been described (Online Mendelian Inheritance in Man (OMIM) 1 ), with more than 150,000 disease- associated variants identified across these disorders in the Human Gene Mutation Database (HGMD) 2 . Despite the success of genome- wide association and whole-exome and whole-genome sequencing (WES/WGS) studies in revealing the DNA variants that underlie the genetic basis of disease, the development of effective treatments for most diseases has remained a challenge. Even for Mendelian disor- ders, only a handful of drugs have been developed 3 . One reason for this lack of success is the difficulty of using small-molecule therapies to restore protein activity in the presence of loss-of-function (LoF) mutations. As a result, treatment of Mendelian disorders typically focuses on the relief of symptoms rather than on a biological ‘cure’. A promising avenue for addressing some of these limitations is to focus analysis on the genetic and environmental modulators that keep people well by suppressing the effects of disease-causing mutations 4 . However, a major challenge in identifying resilient indi- viduals is accurately cataloging disease mutations. Currently, there are no databases that provide a complete characterization of disease genes and their mutations as well as in-depth clinical annotations. For example, the OMIM 1 database contains all known Mendelian disorders with detailed clinical characterizations, but has limited descriptions of disease-causing mutations. In contrast, HGMD 2 has collected almost all disease-associated variants reported to date, but has almost no parameters pertaining to the clinical characteristics attributed to these variants. Furthermore, although many commercial pan-ethnic screening panels cover the most common highly pen- etrant mutations 5–7 , important mutations might be omitted owing to technological limitations and cost-benefit considerations. Also, the exact mutations in these commercial pan-ethnic screening panels are typically inaccessible to the public. Despite these challenges, identification of secondary modulators has proven successful across a multitude of model organisms in which the prominent role of second-site suppressors that buffer or modify traits has been established 8–11 . For example, human genetic studies have identified rare mutations in CCR5 that confer resilience against HIV infection 12 , mutations in globin genes that modify the sever- ity of sickle cell disease by buffering primary mutations in β-globin genes 13 , and LoF mutations in PCSK9 that protect carriers from high lipid levels and resulting heart disease 14 . Second-site mutations in disease genes have also been shown to revert clinical phenotype in patients with recessive dystrophic epidermolysis 15 and Fanconi ane- mia 16 , whereas LoF mutations in zinc transporter 8 have been found to protect obese individuals from diabetes 17 . Most recently, a variant Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases Rong Chen 1,2,12 , Lisong Shi 1,2,12 , Jörg Hakenberg 1,2 , Brian Naughton 3,11 , Pamela Sklar 1,2,4 , Jianguo Zhang 5 , Hanlin Zhou 5 , Lifeng Tian 6 , Om Prakash 7 , Mathieu Lemire 8 , Patrick Sleiman 6 , Wei-yi Cheng 1,2 , Wanting Chen 5 , Hardik Shah 1,2 , Yulan Shen 5 , Menachem Fromer 1,2,4 , Larsson Omberg 9 , Matthew A Deardorff 6 , Elaine Zackai 6 , Jason R Bobe 1,2 , Elissa Levin 1,2 , Thomas J Hudson 8 , Leif Groop 7 , Jun Wang 10 , Hakon Hakonarson 6 , Anne Wojcicki 3 , George A Diaz 1,2 , Lisa Edelmann 1,2 , Eric E Schadt 1,2 & Stephen H Friend 1,2,9 Genetic studies of human disease have traditionally focused on the detection of disease-causing mutations in afflicted individuals. Here we describe a complementary approach that seeks to identify healthy individuals resilient to highly penetrant forms of genetic childhood disorders. A comprehensive screen of 874 genes in 589,306 genomes led to the identification of 13 adults harboring mutations for 8 severe Mendelian conditions, with no reported clinical manifestation of the indicated disease. Our findings demonstrate the promise of broadening genetic studies to systematically search for well individuals who are buffering the effects of rare, highly penetrant, deleterious mutations. They also indicate that incomplete penetrance for Mendelian diseases is likely more common than previously believed. The identification of resilient individuals may provide a first step toward uncovering protective genetic variants that could help elucidate the mechanisms of Mendelian diseases and new therapeutic strategies. 1 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. 2 Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. 3 23andMe, Mountain View, California, USA. 4 Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. 5 BGI-Shenzhen, Shenzhen, China. 6 Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 7 Department of Clinical Sciences, Diabetes & Endocrinology, Lund University Diabetes Center, Skåne University Hospital, Lund University, Malmö, Sweden. 8 Ontario Institute for Cancer Research, Toronto, Ontario, Canada. 9 Sage Bionetworks, Seattle, Washington, USA. 10 iCarbonX, Shenzhen, China. 11 Present address: Boolean Biotech Inc., Mountain View, California, USA. 12 These authors contributed equally to this work. Correspondence should be addressed to E.E.S. (eric.schadt@mssm.edu) or S.H.F. (friend@sagebase.org) or R.C. (rong.chen@mssm.edu). Received 29 July 2015; accepted 12 February 2016; published online 11 April 2016; corrected online 21 April 2016; doi:10.1038/nbt.3514 npg © 2016 Nature America, Inc. All rights reserved.