OBJECTIVES: Patients with rare genetic diseases (RGD) experience a lengthy diagnostic odyssey, involving complex diagnostic testing pathways. Compared to standard genetic tests, whole exome sequencing (WES) has a higher diagnostic yield and has potential to decrease time to diagnosis which is important for patients with suspected RGD and their families. We estimated time-to-diagnosis and cost-effectiveness of WES at different points in the diagnostic pathway.

METHODS: We developed a discrete event simulation model with the standard of care pathway of WES as the second test after a non-WES diagnostic test (Tier 2) and compared four alternative diagnostic pathways: NoWES, and three where WES is the 1^st 3^rd, or 4^th test (Tiers 1,3 and 4, respectively). Each pathway begins with the report of the first test. We compared the performance of the alternative pathways with that of the standard of care (Tier 2). , and expert opinion for the diagnostic yield.

RESULTS: Time-to-diagnosis was longer for each Tier: 1.08, 1.52 and 1.95 years for Tiers 2,3,4 respectively. Average testing costs per patient pathway were CDN$2,412, $2,683, $3,027, $3,720, and $4,292 for NoWES, and Tiers1-4, respectively. Although lower cost, the diagnostic yield of noWES was estimated as 25% compared to 43% for Strategies with WES. The strategy with WES as the first test (Tier1) dominated all other WES strategies – yielding more diagnoses at a lower cost than Tiers 2, 3 or 4.

CONCLUSIONS: Our findings based on testing with WES as the first test in the diagnostic pathway performed better on all measures (shorter time-to-diagnosis increased diagnostic yield, and lower testing costs) than WES at any point later in the diagnostic pathway for patients with suspected RGDs.