Rapid Whole Genome Sequencing Boosts Neurologic Diagnosis

Key Takeaways

• Rapid whole genome sequencing yielded explanatory findings in nearly one quarter of an adult inpatient neurology group.
• Ten findings were pathogenic or likely pathogenic, and four additional variants of uncertain significance were judged explanatory after reverse phenotyping.
• Investigators presented these findings as potentially reducing diagnostic uncertainty, informing management and counseling, and possibly shortening extended diagnostic pathways.

The inpatient neurology group had broad, multifocal disease patterns that raised suspicion for genetic contributors. Patients had prolonged hospitalizations and complex neurologic presentations that remained unexplained after standard evaluation.

The analysis was a retrospective review of hospitalized adults with prolonged stays who underwent rapid whole genome sequencing in Chicago, Illinois. The neurologic subgroup included 58 adults from a larger cohort of 96 hospitalized individuals sequenced between June 2022 and September 2025. Mean age in the neurologic subgroup was 53 years, keeping the analysis within an adult inpatient population rather than a mixed-age series. Investigators focused on patients whose treating teams suspected genetic contributors to multifocal neurologic disease after standard evaluation did not clarify the cause.

Ataxia was the most common feature in the neurologic subgroup, affecting 27% of patients, while epilepsy was reported in 20%. Investigators matched genomic findings to the clinical picture through detailed phenotype evaluation rather than sequence data alone. Ten patients had pathogenic or likely pathogenic variants that aligned with their neurologic presentation. Four additional patients had variants of uncertain significance that were considered explanatory after reverse phenotyping clarified the fit with observed features. All 14 patients with explanatory findings were ultimately found to have monogenic disorders.

Investigators presented the findings as potentially helping direct management, reduce diagnostic uncertainty, and support counseling for patients and families during prolonged admissions. They also suggested that faster genetic explanations could help avoid extended diagnostic pathways in adults with unexplained neurologic manifestations.