First‐Tier Versus Last‐Tier Trio Whole‐Genome Sequencing for the Diagnosis of Pediatric‐Onset Rare Diseases

Le résumé fourni par la source

Despite advances in diagnostics, children with rare genetic disorders still face extended diagnostic odysseys, delaying appropriate clinical management, and placing burdens on families and healthcare resources. Whole-genome sequencing (WGS) offers a more comprehensive interrogation of the genome than other genetic tests, but its use in clinical practice remains limited. This study compared diagnostic rates, turnaround times, and clinical utility of first-tier versus last-tier trio-WGS for patients with suspected genetic pediatric-onset conditions, including 97 critical and 104 non-critical patients. Eighty-five patients (42.3%), including 57 (58.8%) critical and 28 (26.9%) non-critical patients, received a molecular diagnosis. The diagnostic rate was higher for first-tier (57%) than for last-tier (32.8%) trio-WGS. Of 121 causative variants identified, 19.8% would have been missed by whole-exome sequencing. Laboratory processing time was 4 days for all patients. The clinical setting had the greatest impact on time to reporting, averaging 5 days for critical patients versus 74 days for outpatients. WGS results impacted clinical decision-making for 34% of all critical and 14.3% of WGS-positive non-critical patients. This is the first Italian clinical study to demonstrate the diagnostic and clinical utility of a genome-first approach for both critical and non-critical patients with suspected genetic pediatric-onset disorders and feasibility in a public healthcare system.

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