To evaluate the diagnostic yield and clinical relevance of rapid whole genome sequencing (rWGS) in hospitalized adults with unexplained neurological manifestations.

Unexplained neurological presentations in adults often pose diagnostic challenges, leading to prolonged hospitalizations and uncertainty in clinical management. rWGS has emerged as a powerful diagnostic tool to uncover underlying genetic etiologies; however, data on its diagnostic yield in adult inpatient neurology populations remain limited.

We conducted a retrospective review of hospitalized adult patients (≥18 years) with neurological symptoms and prolonged stays who underwent rWGS between June 2022 and September 2025 at Mayo Clinic. rWGS was offered when the primary team suspected a genetic etiology contributing to the patient’s complex and unexplained neurological manifestations. Demographic data, sequencing results, variant classifications, and genotype–phenotype correlations were reviewed and analyzed.

In hospitalized adults with unexplained neurological manifestations, rWGS provided a definitive or likely genetic diagnosis in approximately one-quarter of cases. These findings underscore the clinical utility of rWGS in adult neurology, highlighting its potential to expedite diagnosis, guide management, shorten hospital stays, and inform family counseling.