Guidelines for investigating causality of sequence variants in human disease

Abstract

Acceleration in discovery of rare genetic variants possibly linked with disease may mean an increased risk of false-positive reports of causality; this Perspective proposes guidelines to distinguish disease-causing sequence variants from the many potentially functional variants in a human genome, and to assess confidence in their pathogenicity, and highlights priority areas for development. The wide-scale availability of high-throughput DNA sequencing technologies means that data on genetic variation in human diseases are accumulating rapidly. In this Perspective, Daniel MacArthur and colleagues sound a note of caution, pointing out that up to a quarter of reported disease-linked mutations have been found to either be common polymorphisms or have lacked sufficient evidence for pathogenicity. The authors discuss the key challenges associated with assessing sequence variants in human disease and propose guidelines for the robust differentiation between disease-causing genetic variants and other variants present in the human genome. They highlight several areas where research and resource development are urgently needed if genomic research findings are to be successfully translated into the clinical diagnostic setting. 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.