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.


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).


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.


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%.

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Whole-exome sequencing was funded through a donation by the Kinghorn Foundation to the Garvan Institute of Medical Research. L.J.E. is supported through an Australian Government Research Training Program Scholarship. M.J.C. is supported by Cancer Institute NSW (13/ECF/1-46). T.R. was supported by the Australian National Health and Medical Research Council (APP1117394 Transforming the Diagnosis and Management of Severe Neurocognitive Disorders through Genomics; APP1045465 Gene Identification in Familial Orofacial Clefts by Next Generation Sequencing of Exomes and p63 regulatory elements and an International Biomedical Fellowship 512123 Identification of genes for intellectual disability and brain malformations). We thank the patients, their families, and physicians for their participation in this study. We also thank Jiang Tao, Paula Morris, and Kerith-Rae Dias from the Kinghorn Centre for Clinical Genomics for sequencing these patients.

Author information


  1. St Vincent’s Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia

    • Lisa J Ewans MBBS, BSc
    • , Marcel E Dinger PhD
    •  & Mark J Cowley BSc, PhD
  2. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

    • Lisa J Ewans MBBS, BSc
    • , Deborah Schofield BSpPath, PhD
    • , Velimir Gayevskiy MSc, PhD
    • , Kevin Ying BSc, MBiomedE
    • , David Miller BAppSc
    • , Marcel E Dinger PhD
    •  & Mark J Cowley BSc, PhD
  3. Faculty of Pharmacy, Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia

    • Deborah Schofield BSpPath, PhD
    •  & Rupendra Shrestha MSc, PhD
  4. Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia

    • Deborah Schofield BSpPath, PhD
  5. The Genetics of Learning Disability Service, Waratah, New South Wales, Australia

    • Ying Zhu PhD
    •  & Michael Field MBChB, MPhil
  6. Randwick Genetics, NSW Health Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia

    • Ying Zhu PhD
    • , Corrina Walsh BSc, MHGSA
    • , Eric Lee MBBS, FRCPA
    • , Edwin P Kirk MBBS, PhD
    • , Michael F Buckley MBChB, FRCPA
    •  & Tony Roscioli FRACP, FRCPath
  7. Centre for Clinical Genetics, Sydney Children’s Hospital, Randwick, New South Wales, Australia

    • Edwin P Kirk MBBS, PhD
    • , Carolyn Ellaway MBBS, PhD
    • , Anne Turner MBBS, FRACP
    • , David Mowat MBBS, FRACP
    • , Mary-Louise Freckmann BMed, FRACP
    • , Michelle Lipke MBBS, FRACP
    • , Rani Sachdev MBBS, FRACP
    •  & Tony Roscioli FRACP, FRCPath
  8. School of Women’s and Children’s Health, University of New South Wales, Sydney, New South Wales, Australia

    • Edwin P Kirk MBBS, PhD
    • , Anne Turner MBBS, FRACP
    • , David Mowat MBBS, FRACP
    • , Mary-Louise Freckmann BMed, FRACP
    •  & Rani Sachdev MBBS, FRACP
  9. Clinical Genetics Department, Liverpool Hospital, Liverpool, New South Wales, Australia

    • Alison Colley MBBS, MMedSc
    •  & Lisa Worgan MBBS, MSc
  10. Disciplines of Child and Adolescent Health and Genetic Medicine, University of Sydney, New South Wales, Australia

    • Carolyn Ellaway MBBS, PhD
  11. Lady Cilento Children’s Hospital, Brisbane, Queensland, Australia

    • Michelle Lipke MBBS, FRACP
  12. NeuRA and Prince of Wales Clinical School, University of New South Wales, Kensington, Australia, New South Wales

    • Tony Roscioli FRACP, FRCPath


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L.J.E. and M.E.D. are employees of Genome.One, a whole-owned subsidiary of the Garvan Institute for Medical Research. M.F.B., E.P.K, E.L., and C.W. are employees of Randwick Genetics, NSW Health Pathology East. The other authors declare no conflict of interest.

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Correspondence to Lisa J Ewans MBBS, BSc.

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