Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders

Lisa J Ewans, Deborah Schofield, Rupendra Shrestha, Ying Zhu, Velimir Gayevskiy, Kevin Ying, Corrina Walsh, Eric Lee, Edwin P Kirk, Alison Colley, Carolyn Ellaway, Anne Turner, David Mowat, Lisa Worgan, Mary-Louise Freckmann, Michelle Lipke, Rani Sachdev, David Miller, Michael Field, Marcel E. DingerMichael F Buckley, Mark J Cowley, Tony Roscioli

Research output: Contribution to journalArticlepeer-review

120 Citations (Scopus)


Purpose: Whole-exome sequencing (WES) has revolutionized Mendelian diagnostics, however, there is no consensus on the timing of data review in undiagnosed individuals and only preliminary data on the cost-effectiveness of this technology. We aimed to assess the utility of WES data reanalysis for diagnosis in Mendelian disorders and to analyze the cost-effectiveness of this technology compared with a traditional diagnostic pathway. 

Methods: WES was applied to a cohort of 54 patients from 37 families with a variety of Mendelian disorders to identify the genetic etiology. Reanalysis was performed after 12 months with an improved WES diagnostic pipeline. A comparison was made between costs of a modeled WES pathway and a traditional diagnostic pathway in a cohort with intellectual disability (ID). 

Results: Reanalysis of WES data at 12 months improved diagnostic success from 30 to 41% due to interim publication of disease genes, expanded phenotype data from referrer, and an improved bioinformatics pipeline. Cost analysis on the ID cohort showed average cost savings of US$586 (AU$782) for each additional diagnosis.

Conclusion: Early application of WES in Mendelian disorders is cost-effective and reanalysis of an undiagnosed individual at a 12-month time point increases total diagnoses by 11%.

Original languageEnglish
Pages (from-to)1564-1574
Number of pages11
JournalGenetics in medicine : official journal of the American College of Medical Genetics
Issue number12
Early online date29 Mar 2018
Publication statusPublished - 1 Dec 2018
Externally publishedYes


  • cost-effectiveness
  • diagnosis
  • exome
  • genomics
  • Mendelian


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