Amanat, Man

Importance Rapid whole-genome sequencing (WGS) has advanced inpatient genetic diagnosis, although most evidence comes from neonatal and pediatric intensive care unit (ICU) populations. Its utility for pediatric neurology inpatients across broader acute settings remains insufficiently established. Objective To assess the diagnostic yield, clinical impact, and factors associated with phenotype-concordant rapid WGS diagnoses. Design, Setting, and Participants This was a retrospective cohort study conducted from June 1, 2022, through January 17, 2026, at a tertiary medical center. Pediatric inpatients in the neonatal ICU, pediatric ICU, or general floor with an unexplained neurologic presentation were included. Those with established nongenetic etiology were excluded from analyses. Exposures Trio (77.8%), duo (9.1%), or singleton (13.1%) rapid WGS. Main Outcomes and Measures The primary outcome was the initial phenotype-concordant diagnostic yield at the point of care. Secondary outcomes were reanalysis yield (new diagnoses from reinterpreting nondiagnostic cases prompted by a new unexplained phenotype or family request), cumulative yield, and management change. Associations were assessed by logistic regression (odds ratios [ORs] and 95% CIs). Results Among 175 children (median [IQR] age, 4 months [1 day-4 years]; 93 male [53.1%]) who met inclusion criteria (82 neonates, 93 nonneonates), initial rapid WGS established a phenotype-concordant diagnosis in 79 (45.1%), higher in nonneonates (49 of 93 [52.7%]) than neonates (30 of 82 [36.6%]). Preliminary results returned at mean (SD) 4.0 (1.6) days and final reports at 10.4 (4.5) days. Positive nonconcordant findings occurred in 33 children (18.9%). Reanalysis of 14 nondiagnostic cases yielded 3 additional diagnoses, for a cumulative yield of 82 of 175 children (46.9%). Most diagnoses were monogenic (63 [76.8%]). Management changed in 54 of 82 phenotype-concordant cases (65.9%; 53 at the point of care, 1 after reanalysis) and 8 of 33 (24.2%) positive nonconcordant cases. Family history was most strongly associated with diagnosis (adjusted OR [aOR], 6.46; 95% CI, 3.23-12.93; P < .001), followed by multisystem involvement (aOR, 2.85; 95% CI, 1.24-6.54; P = .01) and congenital anomaly or dysmorphism (aOR, 2.47; 95% CI, 1.07-5.68; P = .03). Hypotonia was most strongly associated in neonates (OR, 20.63; 95% CI, 5.46-77.87; P < .001); ICU admission (OR, 10.25; 95% CI, 2.79-37.67; P < .001) predominated in nonneonates. Conclusions and Relevance Results of this cohort study suggest that rapid WGS diagnosed nearly half of pediatric neurology inpatients and changed management in two-thirds of diagnosed cases, supporting its potential use as early diagnostic testing. Associated features may guide patient selection, and reanalysis extends yield longitudinally.

Background Suicide is the second leading cause of death among children and adolescents, with rates of pediatric suicidal behavior rising substantially over the past two decades. The neurobiology of suicide has been extensively studied in adults, yet pediatric-specific evidence remains limited and the extent to which adult findings can be extrapolated to youth is unclear. This review synthesizes current evidence on the neurobiological correlates of suicidal ideation, suicide attempt, and death by suicide in pediatric and adolescent populations across neurological, genetic, epigenetic, inflammatory, metabolic, and endocrine domains. Methods A literature search was conducted in PubMed, Embase, PsycINFO, and Google Scholar for peer-reviewed, English-language human studies. Priority was given to pediatric and adolescent samples, with adult data included where pediatric evidence was lacking. Studies were grouped by biological domain and by suicidal phenotype. Results Suicidal ideation, suicide attempt, and death by suicide showed partially distinct biological signatures rather than lying on a single continuum of severity. Different markers, most notably cortisol regulation and stress-related DNA methylation, differed in direction between pediatric and adult cohorts, indicating that adult biomarker data cannot be directly extrapolated to youth. Findings converged on a developmental cascade in which genetic liability and early-life adversity influence the hypothalamic-pituitary-adrenal axis, with downstream effects on epigenetic regulation, neuroinflammation, neurochemistry, and frontolimbic circuitry. Conclusions Pediatric suicidal behavior reflects developmentally distinct biological processes that cannot be inferred from adult findings. Advancing the field will require longitudinal, multimodal pediatric studies that disaggregate suicidal phenotypes, span the pubertal transition, and apply age-stratified reference ranges, supporting biologically informed stratification and mechanism-targeted intervention.