Genetics in medicine : official journal of the American College of Medical Genetics · 2025
Comparing the performance of exome and genome sequencing for rare disease diagnostics: A randomized implementation effectiveness trial.
СтатьяРандомизированное исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Hayeems Robin Z, Ungar Wendy J, Marshall Christian R, Gillespie Meredith K, Szuto Anna, Huang Lijia, Venkataramanan Viji, Xiao Bowen, Chisholm Caitlin, Stavropoulos D James, Bergeron Mélanie Beaulieu, Lee Whiwon, Costain Gregory, Jobling Rebekah, Sawyer Sarah, Price E Magda, Lau Lynette, Mendoza Roberto, Somerville Martin J, Boycott Kym M
Аннотация
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 subgroups.
RESULTS: Of 1048 patients, 68.5% had syndromic intellectual disability/developmental delay (ID/DD) and 20.5% had multisystem disorders without ID/DD. Most had prior genetic test(s) that were nondiagnostic (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 < .005). For routine (ie, nonexpedited) 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; however, result type (P < .001) and age of onset (P < .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 diseases.
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 subgroups.
RESULTS: Of 1048 patients, 68.5% had syndromic intellectual disability/developmental delay (ID/DD) and 20.5% had multisystem disorders without ID/DD. Most had prior genetic test(s) that were nondiagnostic (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 < .005). For routine (ie, nonexpedited) 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; however, result type (P < .001) and age of onset (P < .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 diseases.