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Original Investigation
Journal Club
July 31, 2017

Diagnostic Impact and Cost-effectiveness of Whole-Exome Sequencing for Ambulant Children With Suspected Monogenic Conditions

Journal Club PowerPoint Slide Download
Author Affiliations
  • 1Victorian Clinical Genetics Services, Melbourne, Australia
  • 2Murdoch Childrens Research Institute, Melbourne, Australia
  • 3Department of Paediatrics, University of Melbourne, Melbourne, Australia
  • 4Faculty of Pharmacy, University of Sydney, Sydney, Australia
  • 5Garvan Institute of Medical Research, Sydney, Australia
  • 6Melbourne Genomics Health Alliance, Melbourne, Australia
  • 7The Royal Children’s Hospital, Melbourne, Australia
  • 8Walter and Eliza Hall Institute, Melbourne, Australia
JAMA Pediatr. Published online July 31, 2017. doi:10.1001/jamapediatrics.2017.1755
Key Points

Question  What is the clinical impact and cost-effectiveness of whole-exome sequencing in ambulant children suspected of having a monogenic condition?

Findings  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.

Meaning  Pediatricians should consider early referral of children with undiagnosed conditions to clinical genetics specialists for whole-exome sequencing to maximize cost-effectiveness.

Abstract

Importance  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.

Objectives  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.

Exposures  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.

Results  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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