Rapid Whole-Genome Sequencing in Acutely Ill Children: A Single Pediatric Center Experience

Abstract

AbstractThe aim of this study was to describe the turnaround time, diagnostic yield, and clinical impact of rapid whole-genomic sequencing (rWGS). We conducted a prospective observational study in acutely ill children (0–21 years) with an undiagnosed, potentially genetic abnormality in a children's hospital. A phenotype-prioritized analysis approach for rWGS was utilized. The turnaround times, diagnostic yield, number of genes detected, inheritance pattern, zygosity, and the clinical impact of positive or negative tests were analyzed. Out of a total of 109 children, 92 abnormal (pathogenic or likely pathogenic) gene variants were detected in 60 (55%) patients. There were 45 neonates, 35 infants, and 29 children. The admission location was 49.5, 34.9, and 15.6% in the pediatric intensive care unit (PICU), neonatal intensive care unit (NICU), and cardiac intensive care unit (CICU), respectively. The median (interquartile range [IQR]) times for the return of preliminary and final results were 3 (2–5) and 10 (6–14) days, respectively. With ultra-rapid processing, the median time to final results was shorter (5 [3–7] vs. 12 [7.75–15] days). Neurologic issues were the most common underlying admission diagnoses. The diagnostic yield for a causative gene was 47.7%. The diagnostic yield was not different based on age group or location of admission but higher in metabolic issues (78.6 vs. 43.2%; odds ratio [OR]: 4.8; 95% confidence interval [CI]: 1.3–18.4). There was a change in clinical management in 39.4%. In acutely ill children with undiagnosed conditions and with clinical suspicion of a genetic disorder, rWGS detected gene variants in 55% with a diagnostic yield of 47.7% and resulted in a change in the management in 39.4%. The diagnostic yield in patients with metabolic conditions was the highest.