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Guidelines for investigating causality of sequence variants in human disease

Author

Listed:
  • D. G. MacArthur

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of Harvard and MIT)

  • T. A. Manolio

    (National Human Genome Research Institute)

  • D. P. Dimmock

    (Medical College of Wisconsin)

  • H. L. Rehm

    (Laboratory for Molecular Medicine, Partners Healthcare Center for Personalized Genetic Medicine
    Harvard Medical School)

  • J. Shendure

    (University of Washington)

  • G. R. Abecasis

    (University of Michigan)

  • D. R. Adams

    (NIH Undiagnosed Diseases Program, National Institutes of Health Office of Rare Diseases Research and National Human Genome Research Institute
    Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health)

  • R. B. Altman

    (Stanford University)

  • S. E. Antonarakis

    (University of Geneva Medical School, 1211 Geneva, Switzerland
    iGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland)

  • E. A. Ashley

    (Center for Inherited Cardiovascular Disease, Stanford University School of Medicine)

  • J. C. Barrett

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK)

  • L. G. Biesecker

    (Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA)

  • D. F. Conrad

    (Pathology and Immunology, Washington University School of Medicine)

  • G. M. Cooper

    (HudsonAlpha Institute for Biotechnology, 601 Genome Way)

  • N. J. Cox

    (Section of Genetic Medicine, University of Chicago)

  • M. J. Daly

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of Harvard and MIT)

  • M. B. Gerstein

    (Program in Computational Biology and Bioinformatics, Yale University
    Molecular Biophysics and Biochemistry, Yale University)

  • D. B. Goldstein

    (Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina 27708, USA)

  • J. N. Hirschhorn

    (Program in Medical and Population Genetics, Broad Institute of Harvard and MIT
    Children’s Hospital)

  • S. M. Leal

    (Baylor College of Medicine)

  • L. A. Pennacchio

    (MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
    US Department of Energy Joint Genome Institute)

  • J. A. Stamatoyannopoulos

    (University of Washington, 1705 Northeast Pacific Street, Seattle, Washington 98195, USA)

  • S. R. Sunyaev

    (Brigham and Women’s Hospital
    Harvard Medical School)

  • D. Valle

    (McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine)

  • B. F. Voight

    (University of Pennsylvania Perelman School of Medicine)

  • W. Winckler

    (Program in Medical and Population Genetics, Broad Institute of Harvard and MIT
    Present addresses: Next Generation Diagnostics, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA (W.W.); Marcus Autism Center, Children’s Healthcare of Atlanta, Atlanta, Georgia 30329, USA (C.G.).)

  • C. Gunter

    (HudsonAlpha Institute for Biotechnology, 601 Genome Way
    Present addresses: Next Generation Diagnostics, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA (W.W.); Marcus Autism Center, Children’s Healthcare of Atlanta, Atlanta, Georgia 30329, USA (C.G.).)

Abstract

Acceleration in discovery of rare genetic variants possibly linked with disease may mean an increased risk of false-positive reports of causality; this Perspective proposes guidelines to distinguish disease-causing sequence variants from the many potentially functional variants in a human genome, and to assess confidence in their pathogenicity, and highlights priority areas for development.

Suggested Citation

  • D. G. MacArthur & T. A. Manolio & D. P. Dimmock & H. L. Rehm & J. Shendure & G. R. Abecasis & D. R. Adams & R. B. Altman & S. E. Antonarakis & E. A. Ashley & J. C. Barrett & L. G. Biesecker & D. F. Co, 2014. "Guidelines for investigating causality of sequence variants in human disease," Nature, Nature, vol. 508(7497), pages 469-476, April.
    • Handle: RePEc:nat:nature:v:508:y:2014:i:7497:d:10.1038_nature13127
    DOI: 10.1038/nature13127
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    Citations

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    Cited by:

    1. Chang Lu & Jan Zaucha & Rihab Gam & Hai Fang & Smithers & Matt E. Oates & Miguel Bernabe-Rubio & James Williams & Natalie Zelenka & Arun Prasad Pandurangan & Himani Tandon & Hashem Shihab & Raju Kalai, 2023. "Hypothesis-free phenotype prediction within a genetics-first framework," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Bian Li & Dan M. Roden & John A. Capra, 2022. "The 3D mutational constraint on amino acid sites in the human proteome," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Tetsuo Shoda & Kenneth M. Kaufman & Ting Wen & Julie M. Caldwell & Garrett A. Osswald & Pathre Purnima & Nives Zimmermann & Margaret H. Collins & Kira Rehn & Heather Foote & Michael D. Eby & Wenying Z, 2021. "Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Matt C. Danzi & Maike F. Dohrn & Sarah Fazal & Danique Beijer & Adriana P. Rebelo & Vivian Cintra & Stephan Züchner, 2023. "Deep structured learning for variant prioritization in Mendelian diseases," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Wu, Peijie & Chen, Tianyi & Diew Wong, Yiik & Meng, Xianghai & Wang, Xueqin & Liu, Wei, 2023. "Exploring key spatio-temporal features of crash risk hot spots on urban road network: A machine learning approach," Transportation Research Part A: Policy and Practice, Elsevier, vol. 173(C).
    6. Kian Hong Kock & Patrick K. Kimes & Stephen S. Gisselbrecht & Sachi Inukai & Sabrina K. Phanor & James T. Anderson & Gayatri Ramakrishnan & Colin H. Lipper & Dongyuan Song & Jesse V. Kurland & Julia M, 2024. "DNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    7. Jörn Bethune & April Kleppe & Søren Besenbacher, 2022. "A method to build extended sequence context models of point mutations and indels," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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