Abstract
Background: Exome sequencing has been shown to have diagnostic and clinical utility in different disease subgroups, including our previous study involving infants with monogenic disorders. Most published cohorts recruited children at the end of their diagnostic trajectory, having had prior sequencing. Objective: We sought to investigate the impact of exome sequencing in sequencing-naïve children suspected of having a monogenic disorder and evaluate hypothetical changes in their diagnostic trajectory and healthcare costs had exome sequencing been available at an earlier age. Methods: Children aged >2 years suspected of having a monogenic disorder were prospectively recruited from outpatient clinics of The Royal Children's Hospital and Victorian Clinical Genetics Services. All children had non-diagnostic microarrays and no prior single-gene or panel sequencing. We undertook exome sequencing with targeted phenotype-driven analysis and examined the clinical utility of a molecular diagnosis. We also evaluated hypothetical diagnostic trajectories depending on timing of exome sequencing to determine the impact on healthcare costs. Results: We recruited 42 children aged from 2 years 11 months to 18 years and achieved a diagnosis in 19 (45%) by exome sequencing. The average duration of diagnostic trajectory was 6 years, with each child having an average of 19 tests for diagnostic purposes, 4 clinical genetics and 4 non-genetics specialist consultations. We report health economic analyses of exome sequencing offered at the start of the diagnostic trajectory versus standard care. Conclusion: Exome sequencing in outpatient children with suspected monogenic conditions is clinically indicated and should be offered at the start of their diagnostic trajectory.