Guidelines for investigating causality of sequence variants in human disease.


Journal Article

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.

Full Text

Cited Authors

  • 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, 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

Published Date

  • April 2014

Published In

Volume / Issue

  • 508 / 7497

Start / End Page

  • 469 - 476

PubMed ID

  • 24759409

Pubmed Central ID

  • 24759409

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature13127


  • eng