Exome sequencing: dual role as a discovery and diagnostic tool

Ann Neurol. 2012 Jan;71(1):5-14. doi: 10.1002/ana.22647.


Recent developments in high-throughput sequence capture methods and next-generation sequencing technologies have now made exome sequencing a viable approach to elucidate the genetic basis of Mendelian disorders with hitherto unknown etiology. In addition, exome sequencing is increasingly being employed as a diagnostic tool for specific genetic diseases, particularly in the context of those disorders characterized by significant genetic and phenotypic heterogeneity, for example, Charcot-Marie-Tooth disease and congenital disorders of glycosylation. Such disorders are challenging to interrogate with conventional polymerase chain reaction-Sanger sequencing methods, because of the inherent difficulty in prioritizing candidate genes for diagnostic testing. Here, we explore the value of exome sequencing as a diagnostic tool and discuss whether exome sequencing can come to serve a dual role in diagnosis and discovery. We summarize the current status of exome sequencing, the technical challenges facing it, and its adaptation to diagnostics, and make recommendations for the use of exome sequencing as a routine diagnostic tool. Finally, we discuss pertinent ethical concerns, such as the use of exome sequencing data, originally generated in a diagnostic context, in research investigations.

Publication types

  • Review

MeSH terms

  • Animals
  • Charcot-Marie-Tooth Disease / diagnosis
  • Charcot-Marie-Tooth Disease / genetics
  • Exome / genetics*
  • Gene Targeting / ethics
  • Gene Targeting / methods*
  • Gene Targeting / trends*
  • Genome, Human / genetics
  • Humans
  • Sequence Analysis, DNA / ethics
  • Sequence Analysis, DNA / methods*
  • Sequence Analysis, DNA / trends*