Rapid diagnostic whole-genome sequencing has been explored in critically ill newborns, hoping to improve their clinical care and replace time-consuming and/or invasive diagnostic testing. A previous retrospective study in a research setting showed promising results with diagnoses in 57%, but patients were highly selected for known and likely Mendelian disorders. The aim of this prospective study was to assess the speed and yield of rapid targeted genomic diagnostics for clinical application. In 23 critically ill children younger than 12 targeted analysis of 3426 known disease genes was performed by using whole-genome sequencing data. The authors measured diagnostic yield, turnaround times, and clinical consequences. A genetic diagnosis was obtained in 7 patients (30%), with a median turnaround time of 12 days (ranging from 5 to 23 days). Compound heterozygous mutations in the EPG5 gene (Vici syndrome), the RMND1 gene (combined oxidative phosphorylation deficiency-11), and the EIF2B5 gene (vanishing white matter) and homozygous mutations in the KLHL41 gene (nemaline myopathy), the GFER gene (progressive mitochondrial myopathy), and the GLB1 gene (GM1-gangliosidosis) were identified. In addition, a 1p36.33p36.32 microdeletion was detected in a child with cardiomyopathy.
