Guidelines for investigating causality of sequence variants in human disease

被引：925

作者：

MacArthur, D. G. ^{[1
,2
]}

Manolio, T. A. ^{[3
]}

Dimmock, D. P. ^{[4
]}

Rehm, H. L. ^{[5
,6
]}

Shendure, J. ^{[7
]}

Abecasis, G. R. ^{[8
]}

Adams, D. R. ^{[9
,10
,11
]}

Altman, R. B. ^{[12
,13
]}

Antonarakis, S. E. ^{[14
,15
]}

Ashley, E. A. ^{[16
]}

Barrett, J. C. ^{[17
]}

Biesecker, L. G. ^{[18
]}

Conrad, D. F. ^{[19
,20
,21
]}

Cooper, G. M. ^{[22
]}

Cox, N. J. ^{[23
]}

Daly, M. J. ^{[1
,2
]}

Gerstein, M. B. ^{[24
,25
,26
,27
]}

Goldstein, D. B. ^{[28
]}

Hirschhorn, J. N. ^{[2
,29
,30
]}

Leal, S. M. ^{[31
]}

Pennacchio, L. A. ^{[32
,33
]}

Stamatoyannopoulos, J. A. ^{[34
]}

Sunyaev, S. R. ^{[35
,36
]}

Valle, D. ^{[37
]}

Voight, B. F. ^{[38
,39
]}

Winckler, W. ^{[2
]}

Gunter, C. ^{[22
]}

机构：

[1] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[2] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA

[3] NHGRI, Div Genom Med, Bethesda, MD 20892 USA

[4] Med Coll Wisconsin, Dept Pediat, Div Genet, Milwaukee, WI 53226 USA

[5] Partners Healthcare Ctr Personalized Genet Med, Mol Med Lab, Cambridge, MA 02139 USA

[6] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[7] Univ Washington, Dept Genome Sci, Seattle, WA 98115 USA

[8] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[9] NIH, NIH Undiagnosed Dis Program, Off Rare Dis Res, Bethesda, MD 20892 USA

[10] NHGRI, Bethesda, MD 20892 USA

[11] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA

[12] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA

[13] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[14] Univ Geneva, Sch Med, Dept Med Genet, CH-1211 Geneva, Switzerland

[15] iGE3 Inst Genet & Genom Geneva, CH-1211 Geneva, Switzerland

[16] Stanford Univ, Sch Med, Ctr Inherited Cardiovasc Dis, Stanford, CA 94305 USA

[17] Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England

[18] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA

[19] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA

[20] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA

[21] Washington Univ, Sch Med, Dept Immunol, St Louis, MO 63110 USA

[22] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA

[23] Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA

[24] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA

[25] Yale Univ, Dept Comp Sci, New Haven, CT 06520 USA

[26] Yale Univ, Dept Mol Biophys, New Haven, CT 06520 USA

[27] Yale Univ, Dept Biochem, New Haven, CT 06520 USA

[28] Duke Univ, Sch Med, Ctr Human Genome Variat, Durham, NC 27708 USA

[29] Childrens Hosp, Div Genet, Boston, MA 02115 USA

[30] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[31] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[32] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Genom Div, Berkeley, CA 94720 USA

[33] US DOE, Joint Genome Inst, Walnut Creek, CA 94598 USA

[34] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[35] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA

[36] Harvard Univ, Sch Med, Boston, MA 02115 USA

[37] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21287 USA

[38] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA

[39] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA

来源：

NATURE | 2014年 / 508卷 / 7497期

关键词：

DE-NOVO MUTATIONS; RARE VARIANTS; GENES; PHENOTYPE; INDIVIDUALS; ASSOCIATION; POPULATION; DISSECTION; EVOLUTION; GENCODE;

D O I：

10.1038/nature13127

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.

引用

页码：469 / 476

页数：8

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