Abstracts

Rationale: Genetic testing for epilepsy and neurodevelopmental disorders (NDDs) has diagnostic, prognostic and therapeutic implications; however, variant(s) of uncertain significance (VUS) are not actionable. As such, VUS are a challenge to the entire medical community. Here, we report on the prevalence of VUS in patients referred for genetic testing for these conditions and the results of reclassification.


Methods: Patients were referred for genetic testing between September 2014-September 2022. Variants were classified using a validated variant classification framework based on guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). The number of unique VUS (uVUS) and the number of times they were observed in individuals (oVUS) were counted. All-time uVUS were separated as being reclassified and non-reclassified, and the relative impact of evidence types was analyzed.


Results: During this 8-year period, 70,740 unrelated individuals were tested on an epilepsy (up to 302 genes) and/or NDD multigene panel (up to 241 genes) with a mean of 2.0 oVUS per individual. A mean of 2.5 oVUS were observed in 56,751 (80.2%) individuals without a molecular diagnosis. 12.1% (9,000/74,559) uVUS were reclassified, affecting 16,982 individuals (24.0%). 86.4% (7,773/9,000) of reclassified uVUS were downgraded to B/LB and 13.6% (1,227/9,000) were upgraded to LP/P. Clinical observations evidence was enriched 60.0-fold in upgraded uVUS and 41.2-fold in downgraded uVUS when compared with non-reclassified uVUS.


Conclusions: Clinical evidence, including robust patient clinical information and data from family member testing was the most impactful type of evidence in VUS reclassifications. This highlights the partnership between laboratories and clinicians to resolve VUS.


Funding: This work was supported by Invitae.