Guidelines for investigating causality of sequence variants in human disease

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, Don Conrad, G. M. Cooper, N. J. Cox, M. J. Daly, M. B. Gerstein, D. B. Goldstein, J. N. Hirschhorn, S. M. LealL. A. Pennacchio, J. A. Stamatoyannopoulos, S. R. Sunyaev, D. Valle, B. F. Voight, W. Winckler, C. Gunter

Research output: Contribution to journalReview article

692 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)469-476
Number of pages8
JournalNature
Volume508
Issue number7497
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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Causality
Guidelines
Human Genome
Virulence
Research
Genes

ASJC Scopus subject areas

  • General

Cite this

MacArthur, D. G., Manolio, T. A., Dimmock, D. P., Rehm, H. L., Shendure, J., Abecasis, G. R., ... Gunter, C. (2014). Guidelines for investigating causality of sequence variants in human disease. Nature, 508(7497), 469-476. https://doi.org/10.1038/nature13127

Guidelines for investigating causality of sequence variants in human disease. / MacArthur, D. G.; Manolio, T. A.; Dimmock, D. P.; Rehm, H. L.; Shendure, J.; Abecasis, G. R.; Adams, D. R.; Altman, R. B.; Antonarakis, S. E.; Ashley, E. A.; Barrett, J. C.; Biesecker, L. G.; Conrad, Don; Cooper, G. M.; Cox, N. J.; Daly, M. J.; Gerstein, M. B.; Goldstein, D. B.; Hirschhorn, J. N.; Leal, S. M.; Pennacchio, L. A.; Stamatoyannopoulos, J. A.; Sunyaev, S. R.; Valle, D.; Voight, B. F.; Winckler, W.; Gunter, C.

In: Nature, Vol. 508, No. 7497, 01.01.2014, p. 469-476.

Research output: Contribution to journalReview article

MacArthur, DG, Manolio, TA, Dimmock, DP, Rehm, HL, Shendure, J, Abecasis, GR, Adams, DR, Altman, RB, Antonarakis, SE, Ashley, EA, Barrett, JC, Biesecker, LG, Conrad, D, Cooper, GM, Cox, NJ, Daly, MJ, Gerstein, MB, Goldstein, DB, Hirschhorn, JN, Leal, SM, Pennacchio, LA, Stamatoyannopoulos, JA, Sunyaev, SR, Valle, D, Voight, BF, Winckler, W & Gunter, C 2014, 'Guidelines for investigating causality of sequence variants in human disease', Nature, vol. 508, no. 7497, pp. 469-476. https://doi.org/10.1038/nature13127
MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR et al. Guidelines for investigating causality of sequence variants in human disease. Nature. 2014 Jan 1;508(7497):469-476. https://doi.org/10.1038/nature13127
MacArthur, D. G. ; Manolio, T. A. ; Dimmock, D. P. ; Rehm, H. L. ; Shendure, J. ; Abecasis, G. R. ; Adams, D. R. ; Altman, R. B. ; Antonarakis, S. E. ; Ashley, E. A. ; Barrett, J. C. ; Biesecker, L. G. ; Conrad, Don ; Cooper, G. M. ; Cox, N. J. ; Daly, M. J. ; Gerstein, M. B. ; Goldstein, D. B. ; Hirschhorn, J. N. ; Leal, S. M. ; Pennacchio, L. A. ; Stamatoyannopoulos, J. A. ; Sunyaev, S. R. ; Valle, D. ; Voight, B. F. ; Winckler, W. ; Gunter, C. / Guidelines for investigating causality of sequence variants in human disease. In: Nature. 2014 ; Vol. 508, No. 7497. pp. 469-476.
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