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, D. F. 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

724 Scopus citations

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

ASJC Scopus subject areas

  • General

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    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, D. F., Cooper, G. M., Cox, N. J., Daly, M. J., Gerstein, M. B., Goldstein, D. B., Hirschhorn, J. N., ... Gunter, C. (2014). Guidelines for investigating causality of sequence variants in human disease. Nature, 508(7497), 469-476. https://doi.org/10.1038/nature13127