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Guidelines for investigating causality of sequence variants in human disease

MacArthur, DG and Manolio, TA and Dimmock, DP and Rehm, HL and Shendure, J and Abecasis, GR and Adams, DR and Altman, RB and Antonarakis, SE and Ashley, EA and Barrett, JC and Biesecker, LG and Conrad, DF and Cooper, GM and Cox, NJ and Daly, MJ and Gerstein, MB and Goldstein, DB and Hirschhorn, JN and Leal, SM and Pennacchio, LA and Stamatoyannopoulos, JA and Sunyaev, SR and Valle, D and Voight, BF and Winckler, W and Gunter, C (2014) Guidelines for investigating causality of sequence variants in human disease. Nature. pp. 469-476.

Abstract

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. 2014 Macmillan Publishers Limited

Item Type: Article
Additional Information: NIBR author: Winckler, W; Gunter C institute: NIBR- address only contributor address: (MacArthur, Daly) Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States (MacArthur, Daly, Hirschhorn, Winckler) Program in Medical and Population Genetics, Broad Institute of Harvard, MIT, Cambridge, MA 02142, United States (Manolio) Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, MD 20892, United States (Dimmock) Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, United States (Rehm) Laboratory for Molecular Medicine, Partners Healthcare Center for Personalized Genetic Medicine, Cambridge, MA 02139, United States (Rehm) Department of Pathology, Harvard Medical School, Boston, MA 02115, United States (Shendure) Department of Genome Sciences, University of Washington, Seattle, WA 98115, United States (Abecasis) Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, United States (Adams) NIH Undiagnosed Diseases Program, National Institutes of Health, National Human Genome Research Institute, Bethesda, MD 20892, United States (Adams) National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, United States (Altman) Departments of Bioengineering and Genetics, Stanford University, Stanford, CA 94305, United States (Antonarakis) Department of Genetic Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland (Antonarakis) IGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland (Ashley) Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA 94305, United States (Barrett) Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, United Kingdom (Biesecker) Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, United States (Conrad) Departments of Genetics, Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, United States (Cooper, Gunter) HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, United States (Cox) Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, United States (Gerstein) Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, United States (Gerstein) Departments of Computer Science, Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, United States (Goldstein) Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708, United States (Hirschhorn) Divisions of Genetics and Endocrinology, Children's Hospital, Boston, MA 02115, United States (Leal) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States (Pennacchio) Genomics Division, MS84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, United States (Pennacchio) US Department of Energy, Joint Genome Institute, Walnut Creek, CA 94598, United States (Stamatoyannopoulos) Department of Genome Sciences, University of Washington, 1705 Northeast Pacific Street, Seattle, WA 98195, United States (Sunyaev) Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, United States (Sunyaev) Harvard Medical School, Boston, MA 02115, United States (Valle) McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States (Voight) Department of Pharmacology, Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, United States (Winckler) Next Generation Diagnostics, Novartis Institutes for BioMedical Research, Cambridge, MA, United States (Gunter) Marcus Autism Center, Children's Healthcare of Atlanta, Atlanta, GA 30329, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22664

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