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Nat Biotechnol. 2016 May;34(5):531-8. doi: 10.1038/nbt.3514. Epub 2016 Apr 11.

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

Author information

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.

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.

Comment in

PMID:
27065010
DOI:
10.1038/nbt.3514
[Indexed for MEDLINE]

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