Eilbeck Karen, Quinlan Aaron, Yandell Mark
Department of Biomedical Informatics, School of Medicine, University of Utah, 421 Wakara Way, Suite 120, Salt Lake City, Utah 84108, USA.
Department of Human Genetics, Eccles Institute of Human Genetics, School of Medicine, University of Utah, 15 S 2030 E, Salt Lake City, Utah 84112, USA.
Nat Rev Genet. 2017 Oct;18(10):599-612. doi: 10.1038/nrg.2017.52. Epub 2017 Aug 14.
When investigating Mendelian disease using exome or genome sequencing, distinguishing disease-causing genetic variants from the multitude of candidate variants is a complex, multidimensional task. Many prioritization tools and online interpretation resources exist, and professional organizations have offered clinical guidelines for review and return of prioritization results. In this Review, we describe the strengths and weaknesses of widely used computational approaches, explain their roles in the diagnostic and discovery process and discuss how they can inform (and misinform) expert reviewers. We place variant prioritization in the wider context of gene prioritization, burden testing and genotype-phenotype association, and we discuss opportunities and challenges introduced by whole-genome sequencing.
在使用外显子组或基因组测序研究孟德尔疾病时，从众多候选变异中区分致病基因变异是一项复杂的多维度任务。存在许多优先级排序工具和在线解读资源，专业组织也提供了用于审查和返回优先级排序结果的临床指南。在本综述中，我们描述了广泛使用的计算方法的优缺点，解释了它们在诊断和发现过程中的作用，并讨论了它们如何为专家评审提供信息（以及误导信息）。我们将变异优先级排序置于基因优先级排序、负担测试和基因型-表型关联的更广泛背景下，并讨论全基因组测序带来的机遇和挑战。
