Hospitalized adults presenting with unexplained neurological manifestations often experience prolonged diagnostic journeys that delay appropriate management.¹ Although rapid whole genome sequencing (rWGS) has emerged as an important tool for identifying etiologies across multiple neurological disorders, evidence regarding its diagnostic yield in adult inpatient neurology settings remains limited.¹ At the AAN Annual Meeting 2026, Dr. Manouchehr Amanat from the Mayo Clinic presented findings from a retrospective cohort analysis demonstrating that rWGS provided a definitive or likely genetic diagnosis in nearly one-quarter of hospitalized adults with unexplained neurological manifestations.¹ This highlights its potential clinical utility in expediting diagnosis, guiding management, shortening hospital stays, and informing family counseling.¹

Growing evidence supports the role of genetic testing in adults with unexplained neurological disorders, including ataxia, epilepsy, dementia, myopathy, and early-onset Parkinson’s disease.¹ rWGS is a comprehensive genomic approach that assesses coding and noncoding genomic regions through an expedited workflow, enabling clinically actionable results within days.¹ While this approach is extensively investigated in pediatric inpatient populations, data in hospitalized adult neurology patients remain relatively scarce.¹ The study evaluated the diagnostic yield and clinical relevance of rWGS in hospitalized adults aged ≥18 years with unexplained neurological symptoms and prolonged hospital stays between June 2022 and September 2025.¹ The primary outcome was a phenotype-concordant genetic diagnosis capable of explaining the patient’s primary presentation, while secondary outcomes evaluated the clinical impact of rWGS.¹

Among 99 hospitalized adults evaluated by clinical genomics, 96 completed rWGS.¹ Overall, 57 patients were included in the neurological cohort analysis.¹ The mean age was 53.0 ± 18.0 years, and 64.9% were male.¹ Most patients underwent proband-only testing (73.4%), while duo and trio testing were performed in 14.0% and 12.3% of patients, respectively.¹ The most common neurological manifestations were ataxia (27%) and epilepsy (20%).¹

Overall, rWGS identified reportable findings in 43.9% of patients (25/57), including pathogenic or likely pathogenic variants in 15 patients and variants of uncertain significance (VUS) in 10 patients.¹ Following detailed phenotype evaluation, 13 patients (22.8%) obtained phenotype-concordant genetic diagnoses.¹ Among these, 10 patients carried pathogenic or likely pathogenic variants, while 4 had VUS considered clinically explanatory after reverse phenotyping.¹ All genetically diagnosed patients had monogenic disorders.¹ The mean time to diagnosis among these patients was 6.3±12.6 years, underscoring the substantial diagnostic delays frequently encountered.¹

Several clinically relevant genes were identified, including IFIH1, CNBP, C9orf72, NOTCH1, FGF14, NLRP12, CCM2, HEXA, PRNP, and ATXN8OS.¹ Over three-quarters (76.9%) of genetically diagnosed cases demonstrated an autosomal dominant inheritance pattern.¹ Compared with the non-concordant group, phenotype-concordant patients had a significantly higher likelihood of multisystem involvement (46.1% vs. 11.4%; odds ratio [OR]=6.9; p<0.01), family history of similar symptoms (53.8% vs. 13.6%; OR=7.4; p<0.01), refractory psychiatric symptoms (30.8% vs. 6.8%; OR=6.1; p=0.03), and unexplained ataxia (53.8% vs. 22.7%; OR=4.0; p=0.04).¹ In contrast, age, sex, and neuroimaging findings did not predict diagnostic yield.¹

Beyond establishing diagnoses, rWGS demonstrated clinically meaningful impacts.¹ Findings led to the initiation of infliximab therapy in NLRP12-associated disease and enabled referral for a gene therapy trial in HEXA-related Tay-Sachs disease.¹ Additional impacts included anticipatory propranolol initiation in CCM2-related disease and prognostic guidance in PRNP-associated Creutzfeldt-Jakob disease.¹

In summary, rWGS provides meaningful diagnostic utility in hospitalized adults with unexplained neurological manifestations, identifying phenotype-concordant monogenic disorders in approximately one-quarter of patients.¹ Clinical features such as multisystem involvement, family history, and unexplained ataxia optimize patient selection.¹ Despite single-center limitations, the findings support the growing role of rWGS as a high-yield diagnostic tool capable of shortening prolonged journeys and facilitating actionable management.¹