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What is the clinical impact and cost-effectiveness of whole-exome sequencing in ambulant children suspected of having a monogenic condition?
Singleton whole-exome sequencing identified diagnoses in 23 of 44 children (52%); the diagnoses were unexpected in 8 of 23 children (35%), and clinical management was altered in 6 of 23 children (26%). Whole-exome sequencing was most cost-effective when applied at initial presentation to tertiary care compared with first clinical genetics assessment and the standard diagnostic pathway.
Pediatricians should consider early referral of children with undiagnosed conditions to clinical genetics specialists for whole-exome sequencing to maximize cost-effectiveness.
Optimal use of whole-exome sequencing (WES) in the pediatric setting requires an understanding of who should be considered for testing and when it should be performed to maximize clinical utility and cost-effectiveness.
To investigate the impact of WES in sequencing-naive children suspected of having a monogenic disorder and evaluate its cost-effectiveness if WES had been available at different time points in their diagnostic trajectory.
Design, Setting, and Participants
This prospective study was part of the Melbourne Genomics Health Alliance demonstration project. At the ambulatory outpatient clinics of the Victorian Clinical Genetics Services at the Royal Children’s Hospital, Melbourne, Australia, children older than 2 years suspected of having a monogenic disorder were prospectively recruited from May 1 through November 30, 2015, by clinical geneticists after referral from general and subspecialist pediatricians. All children had nondiagnostic microarrays and no prior single-gene or panel sequencing.
All children underwent singleton WES with targeted phenotype-driven analysis.
Main Outcomes and Measures
The study examined the clinical utility of a molecular diagnosis and the cost-effectiveness of alternative diagnostic trajectories, depending on timing of WES.
Of 61 children originally assessed, 44 (21 [48%] male and 23 [52%] female) aged 2 to 18 years (mean age at initial presentation, 28 months; range, 0-121 months) were recruited, and a diagnosis was achieved in 23 (52%) by singleton WES. The diagnoses were unexpected in 8 of 23 (35%), and clinical management was altered in 6 of 23 (26%). The mean duration of the diagnostic odyssey was 6 years, with each child having a mean of 19 tests and 4 clinical genetics and 4 nongenetics specialist consultations, and 26 (59%) underwent a procedure while under general anesthetic for diagnostic purposes. Economic analyses of the diagnostic trajectory identified that WES performed at initial tertiary presentation resulted in an incremental cost savings of A$9020 (US$6838) per additional diagnosis (95% CI, A$4304-A$15 404 [US$3263-US$11 678]) compared with the standard diagnostic pathway. Even if WES were performed at the first genetics appointment, there would be an incremental cost savings of A$5461 (US$4140) (95% CI, A$1433-A$10 557 [US$1086- US$8004]) per additional diagnosis compared with the standard diagnostic pathway.
Conclusions and Relevance
Singleton WES in children with suspected monogenic conditions has high diagnostic yield, and cost-effectiveness is maximized by early application in the diagnostic pathway. Pediatricians should consider early referral of children with undiagnosed syndromes to clinical geneticists.
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Corresponding Author: Clara Gaff, PhD, Melbourne Genomics Health Alliance, 1G Royal Parade, Parkville, Victoria 3052, Australia (firstname.lastname@example.org).
Accepted for Publication: May 1, 2017.
Published Online: July 31, 2017. doi:10.1001/jamapediatrics.2017.1755
Author Contributions: Drs Gaff and White contributed equally to this work. Drs Tan and White had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Tan, Dillon, Stark, Schofield, Alam, Amor, Macciocca, Gaff, White.
Acquisition, analysis, or interpretation of data: Tan, Dillon, Stark, Schofield, Alam, Shrestha, Chong, Phelan, Brett, Creed, Jarmolowicz, Yap, Walsh, Downie, Amor, Savarirayan, McGillivray, Yeung, Peters, Robertson, Robinson, Sadedin, Bell, Oshlack, Georgeson, Thorne, White.
Drafting of the manuscript: Tan, Dillon, Schofield, Alam, Shrestha, Chong, Amor, Robertson, Robinson, Georgeson, White.
Critical revision of the manuscript for important intellectual content: Tan, Stark, Schofield, Alam, Amor, Yeung, Macciocca, Sadedin, Bell, Oshlack, Thorne, Gaff, White.
Statistical analysis: Tan, Dillon, Schofield, Alam, Shrestha, Oshlack, Georgeson.
Obtained funding: Amor, Gaff.
Administrative, technical, or material support: Tan, Dillon, Alam, Phelan, Brett, Creed, Jarmolowicz, Yap, Downie, Yeung, Peters, Robertson, Robinson, Macciocca, Sadedin, Georgeson.
Study supervision: Tan, Stark, Schofield, Oshlack, White.
Conflict of Interest Disclosures: None reported.
Funding/Support: The study was funded by the founding organizations of the Melbourne Genomics Health Alliance (Royal Melbourne Hospital, Royal Children’s Hospital, University of Melbourne, Walter and Eliza Hall Institute, Murdoch Childrens Research Institute, Australian Genome Research Facility, and Commonwealth Scientific and Industrial Research Organisation) and the State Government of Victoria (Department of Health and Human Services). The involvement of Australian Genome Research Facility was supported by sponsorship from Bioplatforms Australia and the National Collaborative Research Infrastructure Strategy program.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.
Additional Contributions: Elin Wee, clinical costings officer at the Royal Children’s Hospital, and Leeanne Cavanough provided administrative support. They were not compensated for their work. We thank all collaborators in the Melbourne Genomics Health Alliance demonstration project.
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