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.

中文翻译：

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解决问题：变异优先顺序和孟德尔病


当使用外显子组或基因组测序研究孟德尔病时，从众多候选变异中区分致病遗传变异是一项复杂的、多维的任务。存在许多优先级划分工具和在线解释资源，并且专业组织提供了用于审查和返回优先级结果的临床指南。在这篇综述中，我们描述了广泛使用的计算方法的优点和缺点，解释了它们在诊断和发现过程中的作用，并讨论了它们如何告知（和误导）专家评审员。我们将变异优先顺序置于基因优先顺序、负荷测试和基因型-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。