Abstract
Translation of genomic sequencing technologies from research to appropriately funded clinical practice requires evidence for cost effectiveness and optimal timing of testing. We report the results of a prospective clinical study that addressed this gap by evaluating the cost effectiveness of singleton whole exome sequencing in 40 infants with suspected monogenic disorders who underwent standard diagnostic investigations in parallel. The mean duration of the diagnostic trajectory was 13 months. A molecular diagnosis was achieved in seven infants (18%) through standard diagnostic care, with a cost per successful diagnosis of AU$27,050 (95% CI: 15,366 to 68,530). By contrast, a molecular diagnosis was achieved in 25 infants (63%) using singleton WES, with a cost per diagnosis of AU$5,047. Integrating singleton WES after exhaustive standard investigation results in an incremental cost per additional diagnosis of AU$8,112 (95% CI: 5,851 to 11,967), whereas integrating WES as a first-line test results in an incremental cost per additional diagnosis of AU$2,182 (95%CI: -5,855 to 130). When used as a first-tier test in infants with suspected monogenic disorders, singleton WES not only outperforms standard diagnostic care in terms of diagnostic utility, but is also most cost-effective.