The purpose of the study was to implement and prospectively evaluate the outcomes of a rapid genomic diagnosis program at two pediatric tertiary centers.


Rapid singleton whole-exome sequencing (rWES) was performed in acutely unwell pediatric patients with suspected monogenic disorders. Laboratory and clinical barriers to implementation were addressed through continuous multidisciplinary review of process parameters. Diagnostic and clinical utility and cost-effectiveness of rWES were assessed.


Of 40 enrolled patients, 21 (52.5%) received a diagnosis, with median time to report of 16 days (range 9–109 days). A result was provided during the first hospital admission in 28 of 36 inpatients (78%). Clinical management changed in 12 of the 21 diagnosed patients (57%), including the provision of lifesaving treatment, avoidance of invasive biopsies, and palliative care guidance. The cost per diagnosis was AU$13,388 (US$10,453). Additional cost savings from avoidance of planned tests and procedures and reduced length of stay are estimated to be around AU$543,178 (US$424,101). The clear relative advantage of rWES, joint clinical and laboratory leadership, and the creation of a multidisciplinary “rapid team” were key to successful implementation.


Rapid genomic testing in acute pediatrics is not only feasible but also cost-effective, and has high diagnostic and clinical utility. It requires a whole-of-system approach for successful implementation.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Stark Z, Tan TY, Chong B et al. A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders. Genet Med 2016;18:1090–1096.

  2. 2

    Daoud H, Luco SM, Li R et al. Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit. CMAJ 2016;188:E254–260.

  3. 3

    Meng L, Pammi M, Saronwala A et al. Use of exome sequencing for infants in intensive care units: ascertainment of severe single-gene disorders and effect on medical management. JAMA Pediatr 2017: e173438.

  4. 4

    Soden SE, Saunders CJ, Willig LK et al. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med 2014;6:265ra168.

  5. 5

    van Diemen CC, Kerstjens-Frederikse WS, Bergman KA et al. Rapid targeted genomics in critically ill newborns. Pediatrics 2017;140:e20162854.

  6. 6

    Willig LK, Petrikin JE, Smith LD et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Resp Med 2015;3:377–387.

  7. 7

    Kingsmore SF, Petrikin J, Willig LK, Guest E. Emergency medical genomes: a breakthrough application of precision medicine. Genome Med 2015;7:82.

  8. 8

    Petrikin JE, Willig LK, Smith LD, Kingsmore SF. Rapid whole genome sequencing and precision neonatology. Semin Perinatol 2015;39:623–631.

  9. 9

    Manolio TA, Abramowicz M, Al-Mulla F et al. Global implementation of genomic medicine: we are not alone. Sci Transl Med 2015;7:290ps13.

  10. 10

    Gaff CL, M Winship I, Forrest SM et al. Preparing for genomic medicine: a real world demonstration of health system change. NPJ Genom Med 2017;2:31.

  11. 11

    Manolio TA, Chisholm RL, Ozenberger B et al. Implementing genomic medicine in the clinic: the future is here. Genet Med 2013;15:258–267.

  12. 12

    Roberts MC, Kennedy AE, Chambers DA, Khoury MJ. The current state of implementation science in genomic medicine: opportunities for improvement. Genet Med 2017;19:858–863.

  13. 13

    Miller NA, Farrow EG, Gibson M et al. A 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases. Genome Med 2015;7:100.

  14. 14

    Monroe GR, Frederix GW, Savelberg SM et al. Effectiveness of whole-exome sequencing and costs of the traditional diagnostic trajectory in children with intellectual disability. Genet Med 2016;18:949–56.

  15. 15

    Stark Z, Schofield D, Alam K et al. Prospective comparison of the cost-effectiveness of clinical whole-exome sequencing with that of usual care overwhelmingly supports early use and reimbursement. Genet Med 2017;19:867–874.

  16. 16

    Walsh M, Bell KM, Chong B et al. Diagnostic and cost utility of whole exome sequencing in peripheral neuropathy. Ann Clin Transl Neurol 2017;4:318–325.

  17. 17

    Vissers LE, van Nimwegen KJ, Schieving JH et al. A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med 2017;19:1055–1063.

  18. 18

    Tan TY, Dillon OJ, Stark Z et al. Diagnostic impact and cost-effectiveness of whole-exome sequencing for ambulant children with suspected monogenic conditions. JAMA Pediatr 2017;171:855–862.

  19. 19

    Girdea M, Dumitriu S, Fiume M et al. PhenoTips: patient phenotyping software for clinical and research use. Hum Mutat 2013;34:1057–1065.

  20. 20

    Stark Z, Dashnow H, Lunke S et al. A clinically driven variant prioritization framework outperforms purely computational approaches for the diagnostic analysis of singleton WES data. Eur J Hum Genet 2017;25:1268–1272.

  21. 21

    Sadedin SP, Dashnow H, James PA et al. Cpipe: a shared variant detection pipeline designed for diagnostic settings. Genome Med 2015;7:68.

  22. 22

    Richards S, Aziz N, Bale S et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–424.

  23. 23

    Damschroder LJ, Aron DC, Keith RE, Kirsh SR, Alexander JA, Lowery JC. Fostering implementation of health services research findings into practice: a consolidated framework for advancing implementation science. Implement Sci 2009;4:50.

  24. 24

    Orlando LA, Sperber NR, Voils C et al. Developing a common framework for evaluating the implementation of genomic medicine interventions in clinical care: the IGNITE Network’s Common Measures Working Group. Genet Med; e-pub ahead of print 14 September 2017.

  25. 25

    Stark Z, Hynson J, Forrester M. Discussing withholding and withdrawing of life-sustaining medical treatment in paediatric inpatients: audit of current practice. J Paediatr Child Health 2008;44:399–403.

  26. 26

    Cohen WM, Levinthal DA. Absorptive-capacity—a new perspective on learning and innovation. Admin Sci Quart 1990;35:128–152.

  27. 27

    Chambers DA, Feero WG, Khoury MJ. Convergence of implementation science, precision medicine, and the learning health care system: a new model for biomedical research. JAMA 2016;315:1941–1942.

  28. 28

    Farwell KD, Shahmirzadi L, El-Khechen D et al. Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med 2015;17:578–586.

  29. 29

    Frankel LA, Pereira S, McGuire AL. Potential psychosocial risks of sequencing newborns. Pediatrics 2016;137(suppl 1):S24–29.

Download references


The study was funded by the founding organizations of the Melbourne Genomics Health Alliance and the State Government of Victoria (Department of Health and Human Services). The involvement of the Australian Genome Research Facility was supported by sponsorship from Bioplatforms Australia and the NCRIS program. We thank the patients and families for participating in this study. We are grateful to Ravi Savarirayan, David Amor, Martin Delatycki, Lilian Downie, Emma Krzesinski, Amanda Moody, David Tingay, Kevin Wheeler, Anastasia Pellicano, Leah Hickey, Ruth Armstrong, Trisha Prentice, and Julia Gunn for referring patients to the study; Amber Boys for cytogenetics support; Michael Tamayo and Audrey Chong for sample processing support; Chris Ieng for bioinformatics support; and Hamidul Huque for statistical support.

Author information


  1. Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, Australia

    • Zornitza Stark BMBCh, DM
    • , Sebastian Lunke PhD
    • , Gemma R Brett MSc
    • , Natalie B Tan MBBS
    • , Rachel Stapleton MB BCh BAO
    • , Smitha Kumble MBBS
    • , Alison Yeung MBBS
    • , Dean G Phelan PhD
    • , Belinda Chong PhD
    • , Miriam Fanjul-Fernandez PhD
    • , Justine E Marum PhD
    • , Anna Jarmolowicz MGenCouns
    • , Jessica R Riseley BSc
    • , Justine Elliott MGenCouns
    • , Tiong Y Tan MBBS, PhD
    •  & Susan M White MBBS
  2. Melbourne Genomics Health Alliance, Melbourne, Australia

    • Zornitza Stark BMBCh, DM
    • , Gemma R Brett MSc
    • , Alison Yeung MBBS
    • , Anna Jarmolowicz MGenCouns
    • , Yael Prawer MGenCouns
    • , Melissa Martyn PhD
    • , Tiong Y Tan MBBS, PhD
    • , Clara L Gaff PhD
    •  & Susan M White MBBS
  3. Department of Paediatrics, University of Melbourne, Melbourne, Australia

    • Zornitza Stark BMBCh, DM
    • , Miriam Fanjul-Fernandez PhD
    • , Melissa Martyn PhD
    • , Tiong Y Tan MBBS, PhD
    • , Clara L Gaff PhD
    •  & Susan M White MBBS
  4. Monash Genetics, Monash Children’s Hospital, Melbourne, Australia

    • Matthew Hunter MB, ChB
    • , Yael Prawer MGenCouns
    •  & Matthew Regan MBBS, PhD
  5. Department of Paediatrics, Monash University, Melbourne, Australia

    • Matthew Hunter MB, ChB
  6. Centre for Healthcare Resilience and Implementation Science, Australian Institute of Health Innovation, Macquarie University, Melbourne, Australia

    • Stephanie Best PhD
  7. Department of Medicine, University of Melbourne, Melbourne, Australia

    • Clara L Gaff PhD


  1. Search for Zornitza Stark BMBCh, DM in:

  2. Search for Sebastian Lunke PhD in:

  3. Search for Gemma R Brett MSc in:

  4. Search for Natalie B Tan MBBS in:

  5. Search for Rachel Stapleton MB BCh BAO in:

  6. Search for Smitha Kumble MBBS in:

  7. Search for Alison Yeung MBBS in:

  8. Search for Dean G Phelan PhD in:

  9. Search for Belinda Chong PhD in:

  10. Search for Miriam Fanjul-Fernandez PhD in:

  11. Search for Justine E Marum PhD in:

  12. Search for Matthew Hunter MB, ChB in:

  13. Search for Anna Jarmolowicz MGenCouns in:

  14. Search for Yael Prawer MGenCouns in:

  15. Search for Jessica R Riseley BSc in:

  16. Search for Matthew Regan MBBS, PhD in:

  17. Search for Justine Elliott MGenCouns in:

  18. Search for Melissa Martyn PhD in:

  19. Search for Stephanie Best PhD in:

  20. Search for Tiong Y Tan MBBS, PhD in:

  21. Search for Clara L Gaff PhD in:

  22. Search for Susan M White MBBS in:


  1. Melbourne Genomics Health Alliance


    The authors declare no conflict of interest.

    Corresponding author

    Correspondence to Zornitza Stark BMBCh, DM.

    Electronic supplementary material

    About this article

    Publication history




    Issue Date


    Further reading