Settling the score: variant prioritization and Mendelian disease

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.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • DNA Copy Number Variations
  • Disease / genetics*
  • Genetic Structures
  • Genetic Variation*
  • Genome, Human
  • Genome-Wide Association Study
  • Humans