Clinical Utility of Rapid Whole-Genome Sequencing in Hospitalized Adults With Unexplained Neurologic Presentations

Background and Objectives – Adults with unexplained neurologic presentations often undergo extensive evaluations without timely diagnosis. Evidence supporting the clinical utility of rapid whole-genome sequencing (rWGS) in hospitalized adult populations remains limited. We evaluated the diagnostic yield of rWGS in adults hospitalized for unexplained neurologic manifestations and assessed clinical predictors of a phenotype-concordant genetic diagnosis.Methods – We performed a retrospective cohort analysis of adult inpatients (≥18 years) undergoing rWGS as part of a structured inpatient clinical genomics implementation at Mayo Clinic between June 2022 and September 2025. Testing was performed after primary team consultation and subsequent assessment by a clinical geneticist. We prespecified a neurologic cohort restricted to patients admitted to the neurology inpatient service in whom presenting neurologic phenotypes were the primary indication for hospitalization and genomics consultation. Patients with non-neurologic primary indications were excluded from this study. The primary outcome was a phenotype-concordant genetic diagnosis on rWGS determined by genotype-phenotype assessment. Analytic objectives included identification of clinical predictors of a phenotype-concordant genetic diagnosis, and a secondary outcome was rWGS-attributable changes in clinical management. Patients with and without phenotype-concordant diagnoses were compared using univariable logistic regression for categorical candidate predictors (odds ratios [ORs] with 95% CIs) and the t test for age.Results – Among 96 adults who completed rWGS, 57 (59.4%) met criteria for the neurologic cohort (mean age 53.0 ± 18.0 years; 35.1% female). Thirteen of 57 (22.8%) received a phenotype-concordant genetic diagnosis involving IFIH1, CNBP, NOTCH1, C9orf72, FGF14, HUWE1, NLRP12, CCM2, PTPN11, FLNA, HEXA, PRNP, and ATXN8OS. Factors associated with a phenotype-concordant diagnosis included a family history of similar neurologic symptoms in first-degree or second-degree relatives (OR 7.4; 95% CI 1.9–31.5), multisystem involvement (OR 6.9; 95% CI 1.6–29.8), refractory psychiatric symptoms (OR 6.1; 95% CI 1.1–35.7), and unexplained ataxia (OR 4.0; 95% CI 1.1–15.1). rWGS directly altered clinical management in 2 cases, including initiation of immunotherapy for an NLRP12-associated autoinflammatory disorder and enrollment in a gene-therapy trial for adult-onset Tay-Sachs disease.Discussion – In this tertiary-care inpatient cohort, rWGS identified a phenotype-concordant genetic diagnosis in nearly one-quarter of adults. Limitations include single-center design and preselection through specialized consultation, which may limit generalizability.