Investigating the frequency of unreported cases and laboratory correspondence practices for variants of uncertain significance in pediatric epilepsy

Genetic testing via multigene panels has become common practice for children with epilepsy. This results in frequent identification of variants of uncertain significance (VUS). Providers must then assess clinical suspicion of the VUS, considering clinical correlation, family variant testing, and laboratory contact for internal case data. Labs often have seen previous cases of a VUS with variant and clinical information kept in their records internally; cases that go unused in variant classification due to requirements established by the American College of Medical Genetics (ACMG) variant classification guidelines. This study aims to better understand the frequency at which internal case data is suspected based on a VUS report and to evaluate provider practice around obtaining and documenting such data. We conducted a retrospective chart review of pediatric patients at the University of Utah and Intermountain Primary Children Hospital's Neurology clinic who underwent epilepsy panel testing in 2022. Review of a total of 261 reports identified 265 VUSs in an autosomal dominant or X-linked gene across 162 patients. We found that internal cases were suspected for 122 of the 265 (46.0%) variants, with most of these variants lacking clear documentation of internal cases on the report. Chart documentation of laboratory contact existed for only 9 of 122 (7.3%) variants with suspected internal cases. VUSs on the epilepsy gene panel commonly have undocumented internal cases at the reporting laboratory. Knowledge of this unreported data is important for providers to determine when laboratory contact is appropriate and to develop guidelines for documentation. PLAIN LANGUAGE SUMMARY: Genetic tests, routinely done for epilepsy, often find changes in genes called variants of uncertain significance (VUS) that require follow-up for providers to interpret. Laboratories may have seen these variants previously in other patients and have information that may be helpful in clinical interpretation that they cannot included in the test report. In our review of children tested for epilepsy, almost half of the VUS had suspected, unreported information at the lab, but providers rarely contacted the lab to ask for it. Better awareness and guidelines may help providers access and document this information to help guide patient care.