Rare-disease genetics in the era of next-generation sequencing: discovery to translation

Nat Rev Genet. 2013 Oct;14(10):681-91. doi: 10.1038/nrg3555. Epub 2013 Sep 3.


Work over the past 25 years has resulted in the identification of genes responsible for ~50% of the estimated 7,000 rare monogenic diseases, and it is predicted that most of the remaining disease-causing genes will be identified by the year 2020, and probably sooner. This marked acceleration is the result of dramatic improvements in DNA-sequencing technologies and the associated analyses. We examine the rapid maturation of rare-disease genetic analysis and successful strategies for gene identification. We highlight the impact of discovering rare-disease-causing genes, from clinical diagnostics to insights gained into biological mechanisms and common diseases. Last, we explore the increasing therapeutic opportunities and challenges that the resulting expansion of the 'atlas' of human genetic pathology will bring.

Publication types

  • Review

MeSH terms

  • Genetic Predisposition to Disease
  • Genetic Testing
  • Genetics, Medical
  • Genome, Human / genetics*
  • Genome-Wide Association Study
  • High-Throughput Nucleotide Sequencing* / trends
  • Humans
  • Mutation
  • Rare Diseases / genetics*
  • Rare Diseases / therapy
  • Sequence Analysis, DNA