Rapid Whole-Genome Sequencing Yielded Diagnoses in Nearly Half of Pediatric Neurology Inpatients

Rapid whole-genome sequencing (WGS) established a phenotype-concordant diagnosis in nearly half of pediatric neurology inpatients and changed management in about two-thirds of diagnosed cases, according to a retrospective cohort study published in JAMA Neurology.

The investigators noted that most evidence for rapid WGS comes from neonatal and pediatric intensive care unit (ICU) populations. The study, conducted at a tertiary medical center from June 2022 through January 2026, included inpatients in the neonatal ICU, pediatric ICU, or general floor with an unexplained neurologic presentation. Patients with an established nongenetic etiology were excluded. Most underwent trio sequencing (77.8%), followed by singleton (13.1%) and duo (9.1%) sequencing.

Among 175 children (median age, 4 months), initial rapid WGS yielded a phenotype-concordant diagnosis in 79 (45.1%), with a higher yield in nonneonates (52.7%) than in neonates (36.6%). Preliminary results returned at a mean of 4.0 days and final reports at 10.4 days. Reanalysis of 14 nondiagnostic cases yielded 3 additional diagnoses, for a cumulative yield of 46.9%. Most diagnoses (76.8%) were monogenic.

Management changed in 54 of 82 phenotype-concordant cases (65.9%) and in 8 of 33 cases with positive nonconcordant findings (24.2%). Family history was most strongly associated with diagnosis (adjusted odds ratio [aOR], 6.46; 95% CI, 3.23-12.93), followed by multisystem involvement (aOR, 2.85; 95% CI, 1.24-6.54) and congenital anomaly or dysmorphism (aOR, 2.47; 95% CI, 1.07-5.68). Hypotonia was most strongly associated with diagnosis in neonates, and ICU admission in nonneonates.

The authors wrote that the results support the "potential use" of rapid WGS as early diagnostic testing and that associated features may guide patient selection. The findings come from a retrospective, single-center analysis.

Source: Amanat M, Ali A, Tan Q, et al. Rapid whole-genome sequencing in pediatric neurology inpatients. JAMA Neurol. Published online October 5, 2026. doi:10.1001/jamaneurol.2026.3410