Evaluating systematic reanalysis of clinical genomic data in rare disease from single center experience and literature review

Mol Genet Genomic Med. 2020 Nov;8(11):e1508. doi: 10.1002/mgg3.1508. Epub 2020 Sep 23.


Background: Our primary aim was to evaluate the systematic reanalysis of singleton exome sequencing (ES) data for unsolved cases referred for any indication. A secondary objective was to undertake a literature review of studies examining the reanalysis of genomic data from unsolved cases.

Methods: We examined data from 58 unsolved cases referred between June 2016 and March 2017. First reanalysis at 4-13 months after the initial report considered genes newly associated with disease since the original analysis; second reanalysis at 9-18 months considered all disease-associated genes. At 25-34 months we reviewed all cases and the strategies which solved them.

Results: Reanalysis of existing ES data alone at two timepoints did not yield new diagnoses. Over the same timeframe, 10 new diagnoses were obtained (17%) from additional strategies, such as microarray detection of copy number variation, repeat sequencing to improve coverage, and trio sequencing. Twenty-seven peer-reviewed articles were identified on the literature review, with a median new diagnosis rate via reanalysis of 15% and median reanalysis timeframe of 22 months.

Conclusion: Our findings suggest that an interval of greater than 18 months from the original report may be optimal for reanalysis. We also recommend a multi-faceted strategy for cases remaining unsolved after singleton ES.

Keywords: exome sequencing; genome sequencing; rare disease; reanalysis.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Genetic Testing / methods
  • Genetic Testing / standards*
  • Humans
  • Rare Diseases / diagnosis
  • Rare Diseases / genetics*
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Sequence Analysis, DNA / methods
  • Sequence Analysis, DNA / standards*
  • Whole Exome Sequencing / methods
  • Whole Exome Sequencing / standards*