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

被引：226

作者：

Chen, Rong ^{[1
,2
]}

Shi, Lisong ^{[1
,2
]}

Hakenberg, Joerg ^{[1
,2
]}

Naughton, Brian ^{[3
,12
]}

Sklar, Pamela ^{[1
,2
,4
,5
]}

Zhang, Jianguo ^{[6
]}

Zhou, Hanlin ^{[6
]}

Tian, Lifeng ^{[7
]}

Prakash, Om ^{[8
]}

Lemire, Mathieu ^{[9
]}

Sleiman, Patrick ^{[7
]}

Cheng, Wei-yi ^{[1
,2
]}

Chen, Wanting ^{[6
]}

Shah, Hardik ^{[1
,2
]}

Shen, Yulan ^{[6
]}

Fromer, Menachem ^{[1
,2
,4
,5
]}

Omberg, Larsson ^{[10
]}

Deardorff, Matthew A. ^{[7
]}

Zackai, Elaine ^{[7
]}

Bobe, Jason R. ^{[1
,2
]}

Levin, Elissa ^{[1
,2
]}

Hudson, Thomas J. ^{[9
]}

Groop, Leif ^{[8
]}

Wang, Jun ^{[11
]}

Hakonarson, Hakon ^{[7
]}

Wojcicki, Anne ^{[3
]}

Diaz, George A. ^{[1
,2
]}

Edelmann, Lisa ^{[1
,2
]}

Schadt, Eric E. ^{[1
,2
]}

Friend, Stephen H. ^{[1
,2
,10
]}

机构：

[1] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA

[3] 23andMe, Mountain View, CA USA

[4] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA

[5] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[6] BGI Shenzhen, Shenzhen, Peoples R China

[7] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[8] Lund Univ, Skane Univ Hosp, Lund Univ Diabet Ctr, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden

[9] Ontario Inst Canc Res, Toronto, ON, Canada

[10] Sage Bionetworks, Seattle, WA USA

[11] ICarbonX, Shenzhen, Peoples R China

[12] Boolean Biotech Inc, Mountain View, CA USA

来源：

NATURE BIOTECHNOLOGY | 2016年 / 34卷 / 05期

基金：

美国国家卫生研究院;

关键词：

AUTOSOMAL SEX REVERSAL; CAMPOMELIC DYSPLASIA; COMMON MUTATION; GENE; VARIANTS; PHENOTYPE; MEDICINE; PATIENT; CANCER; IMPACT;

D O I：

10.1038/nbt.3514

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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.

引用

页码：531 / 538

页数：8

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