Guidelines for investigating causality of sequence variants in human disease

Nature

508,

469–476

(24 April 2014)

doi:10.1038/nature13127

Received: 24 June 2013
Accepted: 05 February 2014
Published online: 23 April 2014

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.

Subject terms:

Genetic testing

High-throughput sequencing approaches can generate detailed catalogues of genetic variation in both disease patients and the general population. However, for these technologies to have the greatest medical impact we must be able to separate genuine disease-causing or disease-associated genetic variants reliably from the broader background of variants present in all human genomes that are rare, potentially functional, but not actually pathogenic (Box 1) for the disease or phenotype under investigation.