Efficiency of whole exome/genome sequencing for achieving a diagnosis in rare presentations. M. C. Towne1, A. H. Beggs1, 2, P. B. Agrawal1, 2 1) The Manton Center for Orphan Disease Research, Division of Genetics, Children's Hospital Boston, Boston, MA; 2) Harvard Medical School, Boston, MA.

   To measure the cost effectiveness and efficiency of whole exome/genome sequencing (WES/WGS) compared to targeted gene analysis in a pediatric population with an undiagnosed potentially genetic disease. We analyzed the molecular diagnostic process of individuals enrolled in The Manton Center for Orphan Disease Research Gene Discovery Core, a repository for individuals with undiagnosed and rare conditions. DNA from 103 families was sent for WES or WGS analysis. Of the 99 datasets returned, we have completed analysis for 45 families. Ten of these patients received a genetic diagnosis after enrollment through either research WES/WGS or clinical targeted gene analysis. By tabulating the number of target genes/gene panels sequenced in each of these patients prior to obtaining a genetic diagnosis, associated time and costs, we can estimate the relative efficiencies of traditional genetic diagnostic and WES/WGS approaches. Here, we present preliminary data on 5 of these 10 families. Two patients were diagnosed by targeted sequencing while 3 were diagnosed by WES/WGS. We saw shorter turnaround times between initial presentation and diagnosis for the participants who had a diagnosis found by research WES/WGS (210 days) versus those diagnosed by targeted analysis (605.5 days). The average number of genetics clinic visits to obtain a diagnosis was 6, and the number of targeted molecular tests performed per patient prior to a genetic diagnosis was 9.5. We expect the cost for WES/WGS, even when sending trios for analysis (average of $3,700 USD for WES per family) to be less than the targeted gene analysis approach. Further analysis of the cost per test is underway. Of significance, in the 3 year period examined, the cost of exome sequencing has decreased by nearly 50% ($1,999 to $1,025). Analysis did not include costs associated with additional duration of stay, other tests, administrative/visit fees and parental stress due to delays in diagnosis. In one patient, WGS data did not confirm the mutation identified by targeted sequencing. Our preliminary data suggests that WES/WGS is an efficient and likely cost-effective way of diagnosing the genetic basis of disease compared to targeted sequencing. These findings are reflective of research testing, and WES/WGS would likely have a shorter turnaround time when handled in a more automated clinical laboratory. In our cohort, genetic diagnoses were identified in 22% of the 45 families, demonstrating limitations of WES/WGS.

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