Genet Med. 2025 Oct 10:101605. doi: 10.1016/j.gim.2025.101605. Online ahead of print.
ABSTRACT
PURPOSE: Exome sequencing (ES) and genome sequencing (GS) can improve rare disease diagnosis but are not routinely available in many jurisdictions. To inform implementation, we report on a randomized implementation effectiveness trial comparing ES and GS.
METHODS: Eligible trios were randomized to receive ES or GS in the same clinically accredited laboratory. Patient-level data on diagnostic utility and turnaround times were collected. Outcomes were compared statistically between clinically important sub-groups.
RESULTS: Of 1048 patients, 68.5% had syndromic intellectual disability/developmental delay (ID/DD) and 20.5% had multi-system disorders without ID/DD. Most had prior genetic test(s) that were non-diagnostic (95.5%) and of these, 91.6% included chromosome microarray. Diagnostic yields were 33.8% and 33.6%, for ES (n=526) and GS (n=522), respectively. Within sequencing groups, diagnostic results were more frequent among those with ID/DD than those without (p<0.005). For routine (i.e., non-expedited) patients (n=1020), 87.0% were reported in <12 weeks and the mean turnaround time was 55.5 days (SD: 24.0). Turnaround time for ES and GS did not differ but result type (p<0.001) and age of onset (p<0.005) significantly affected turnaround time.
CONCLUSION: Findings provide robust evidence of diagnostic utility and timeliness of ES and GS and will inform policy related to the organization, delivery, and reimbursement of clinical-grade genome diagnostics for rare disease.
PMID:41084864 | DOI:10.1016/j.gim.2025.101605
