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Nature DOI:10.1038/nature13127

Guidelines for investigating causality of sequence variants in human disease.

Publication TypeJournal Article
Year of Publication2014
AuthorsMacarthur, DG, Manolio, TA, Dimmock, DP, Rehm, HL, Shendure, J, Abecasis, GR, Adams, DR, Altman, RB, Antonarakis, SE, Ashley, EA, Barrett, JC, Biesecker, LG, Conrad, DF, 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
Date Published2014/04/24

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.