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

Abstract

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. 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 <i>t</i> test for age. 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 <i>IFIH1</i>, <i>CNBP</i>, <i>NOTCH1</i>, <i>C9orf72</i>, <i>FGF14</i>, <i>HUWE1</i>, <i>NLRP12</i>, <i>CCM2</i>, <i>PTPN11</i>, <i>FLNA</i>, <i>HEXA</i>, <i>PRNP</i>, and <i>ATXN8OS</i>. 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 <i>NLRP12</i>-associated autoinflammatory disorder and enrollment in a gene-therapy trial for adult-onset Tay-Sachs disease. 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.