domingo, 27 de abril de 2014

Guidelines for investigating causality of sequence variants in human disease : Nature : Nature Publishing Group

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Guidelines for investigating causality of sequence variants in human disease : Nature : Nature Publishing Group



Guidelines for investigating causality of sequence variants in human disease

Nature
 
508,
 
469–476
 
 
doi:10.1038/nature13127
Received
 
Accepted
 
Published online
 
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.
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.

Box 1: Terms used to describe sequence variants

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