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Nat Rev Genet. 2017 Oct;18(10):599-612. doi: 10.1038/nrg.2017.52. Epub 2017 Aug 14.

Settling the score: variant prioritization and Mendelian disease.

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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.


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.

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