title: Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases.
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.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Rong
authors.identifier: 0000-0001-6322-0340
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Lisong
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hakenberg
authors.affiliation: 23andMe, Mountain View, California, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Naughton
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Sklar
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhang
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Hanlin
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Lifeng
authors.identifier: 0000-0003-1880-5811
authors.initials: L
authors.lastname: Tian
authors.affiliation: Department of Clinical Sciences, Diabetes &Endocrinology, Lund University Diabetes Center, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Om
authors.initials: O
authors.lastname: Prakash
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lemire
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sleiman
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Cheng
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Wanting
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Hardik
authors.initials: H
authors.lastname: Shah
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Yulan
authors.identifier: 0000-0002-2866-4146
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Menachem
authors.identifier: 0000-0003-3749-4342
authors.initials: M
authors.lastname: Fromer
authors.affiliation: Sage Bionetworks, Seattle, Washington, USA.
authors.forename: Larsson
authors.initials: L
authors.lastname: Omberg
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Zackai
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Bobe
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Elissa
authors.initials: E
authors.lastname: Levin
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Thomas J
authors.identifier: 0000-0002-1376-4849
authors.initials: TJ
authors.lastname: Hudson
authors.affiliation: Department of Clinical Sciences, Diabetes &Endocrinology, Lund University Diabetes Center, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: iCarbonX, Shenzhen, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: 23andMe, Mountain View, California, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Wojcicki
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Diaz
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Edelmann
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Sage Bionetworks, Seattle, Washington, USA.
authors.forename: Stephen H
authors.identifier: 0000-0002-0830-7600
authors.initials: SH
authors.lastname: Friend
mesh_terms: D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping / Q000379:methods* / Q000706:statistics & numerical data; D004252:DNA Mutational Analysis / Q000379:methods; D060467:Disease Resistance / Q000235:genetics*; D005260:Female; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D057182:Mendelian Randomization Analysis / Q000379:methods* / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity