Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers

Genet Med. 2017 Feb;19(2):209-214. doi: 10.1038/gim.2016.88. Epub 2016 Jul 21.


Purpose: Clinical exome sequencing is nondiagnostic for about 75% of patients evaluated for a possible Mendelian disorder. We examined the ability of systematic reevaluation of exome data to establish additional diagnoses.

Methods: The exome and phenotypic data of 40 individuals with previously nondiagnostic clinical exomes were reanalyzed with current software and literature.

Results: A definitive diagnosis was identified for 4 of 40 participants (10%). In these cases the causative variant is de novo and in a relevant autosomal-dominant disease gene. The literature to tie the causative genes to the participants' phenotypes was weak, nonexistent, or not readily located at the time of the initial clinical exome reports. At the time of diagnosis by reanalysis, the supporting literature was 1 to 3 years old.

Conclusion: Approximately 250 gene-disease and 9,200 variant-disease associations are reported annually. This increase in information necessitates regular reevaluation of nondiagnostic exomes. To be practical, systematic reanalysis requires further automation and more up-to-date variant databases. To maximize the diagnostic yield of exome sequencing, providers should periodically request reanalysis of nondiagnostic exomes. Accordingly, policies regarding reanalysis should be weighed in combination with factors such as cost and turnaround time when selecting a clinical exome laboratory.Genet Med 19 2, 209-214.

Publication types

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

MeSH terms

  • Child
  • Child, Preschool
  • Exome / genetics
  • Female
  • Genetic Diseases, Inborn / diagnosis*
  • Genetic Diseases, Inborn / genetics*
  • Genetic Diseases, Inborn / pathology
  • Genetics, Medical / standards*
  • Humans
  • Infant
  • Male
  • Mutation
  • Pedigree
  • Sequence Analysis, DNA
  • Whole Exome Sequencing / standards*