Cited by 314Genomics and Rare DiseasesGenetic Associations and EpidemiologyEvolution and Genetic Dynamics

Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases

Chen, Rong, Shi, Lisong, Hakenberg, Jörg, Naughton, Brian, Sklar, Pamela, Zhang, Jianguo, Zhou, Hanlin, Tian, Lifeng +22 more·2016·Nature Biotechnology

Abstract

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.

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Crossref · 10.1038/nbt.3514

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Authors
Chen, R., Shi, L., Hakenberg, J., Naughton, B., Sklar, P., Zhang, J., Zhou, H., Tian, L., Prakash, O., Lemire, M., Sleiman, P., Cheng, W.-Y., Chen, W., Shah, H., Shen, Y., Fromer, M., Omberg, L., Deardorff, M. A., Zackai, E., Bobe, J. R., Levin, E., Hudson, T. J., Groop, L., Wang, J., Hakonarson, H., Wojcicki, A., Diaz, G. A., Edelmann, L., Schadt, E. E., & Friend, S. H.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • 23andMe (United States) (US)
  • BGI Group (China) (CN)
  • Children's Hospital of Philadelphia (US)
  • Lund University (SE)
  • Ontario Institute for Cancer Research (CA)
  • Sage Bionetworks (US)
Corresponding author
  • Chen, Rong
  • Schadt, Eric E
  • Friend, Stephen H
Venue
Nature Biotechnology
Published
2016-04-11
Volume
34
Issue
5
Pages
531-538
ISSN
  • 0733-222X (ISSN-L)
  • 1087-0156
  • 1546-1696
OpenAlex
W2326403029
Cited by
310
References
59
Citations by year
2026: 14 · 2025: 19 · 2024: 13 · 2023: 33 · 2022: 24 · 2021: 26 · 2020: 38 · 2019: 33 · 2018: 32 · 2017: 45 · 2016: 33
FWCI
38.51
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Biotechnology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
Keywords
disease resilience, asymptomatic carriers, incomplete penetrance, protective genetic variants, pathogenic variants
MeSH terms
Child, Child, Preschool, Chromosome Mapping, DNA Mutational Analysis, Female, Genetic Testing, Humans, Infant, Infant, Newborn, Male, Sensitivity and Specificity, Reproducibility of Results, Genome, Human, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genetic Diseases, Inborn, Mendelian Randomization Analysis, Disease Resistance

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