Enhancing Variant of Uncertain Significance (VUS) Interpretation in Neurogenetics: Collaborative Experiences from a Tertiary Care Centre

Background: The findings of variants of uncertain significance (VUS) on a clinical genetic testing report pose a challenge for attending healthcare professionals (HCPs) in patient care. Here, we describe the outcomes of multidisciplinary VUS Rounds, implemented at a neurological disease tertiary care centre, which aid in interpreting and communicating VUS identified in our neurogenetics patient population. Methods: VUS Rounds brought together genetic counsellors, molecular geneticists, and scientists to evaluate VUS against genomic and phenotypic evidence and assign an internal temperature classification "VUS Hot", "True VUS", or "VUS Cold", corresponding to potential pathogenicity. Biweekly meetings were held among the committee to deliberate variant classifications, determine additional clinical management actions, and discuss nuances of VUS result communication. Results: In total, 143 VUS identified in 72 individuals with neurological disease were curated between October 2022 and December 2023. Of these, 12.6% were classified as VUS Hot, carried by 22.2% of the individuals, allowing for prioritization of additional evaluation to determine potential pathogenicity of the variants, such as clinical follow-up or segregation analysis. In contrast, 45.4% of VUS were Cold and could be eliminated from further consideration in the carrier's care. Herein, we thoroughly evaluated the various evidence that contributed to our VUS classifications and resulting clinical actions. Conclusions: The assessment of VUS leveraging multidisciplinary collaboration allowed us to delineate required follow-up analyses for our neurology patient population. Integration of VUS Rounds into healthcare practices, ensures equitable knowledge dissemination amongst HCPs and effective incorporation of uncertain genetic results into patient care.