Nature2014-06-18 6:00 PM

遗传变异和人类疾病 Guidelines for investigating causality of sequence variants in human disease

论文摘要 

高吞吐量DNA测序技术的广泛普及意味着,关于人类疾病中的遗传变异的数据在迅速积累。在这篇Perspective文章中,Daniel MacArthur及同事发出警告,指出所报告的与疾病相关的突变中近1/4已被发现要么是普通的多态型,要么没有足够的证据来证明其能够致病。作者讨论了与评估人类疾病中的序列变体相关的关键挑战,提出了用来可靠区分人类基因组中致病性基因变体与其他变体的方针。他们指出了如果要将基因组研究成果成功应用到临床诊断中去则急需进行研究和资源开发的几个领域。

Abstract 

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.

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