Purpose of Review To describe the clinical implications of genetic diagnoses in epilepsy and the recent advancements in this field. Recent Findings A genetic diagnosis in epilepsy has been shown to impact clinical management in almost half of individuals, often within three months of diagnosis, with anti-seizure medication recommendations being the most common change. More recently, data from somatic genetic testing in brain tissue has shown the potential to impact prognostic information and medication recommendations. Summary Genetic testing is becoming routine clinical care in epilepsy and is recommended for all individuals with unexplained epilepsy, regardless of age. A monogenic epilepsy diagnosis impacts clinical seizure management and provides additional non-seizure management benefits. The clinical utility of genetic testing will only continue to increase as gene therapies and other precision medicine treatments are approved.

Background/Objectives: To characterize the clinical and imaging phenotypes of schwannomatosis (SWN) in children, adolescents, and young adults (AYAs). Methods: This single-center retrospective cohort study included patients (age ≤ 25 years) with suspected SWN with archived magnetic resonance imaging (MRI) at Johns Hopkins between 2020–2026. Clinical characteristics, genetic testing results, and tumor imaging (including anatomic distribution), and treatment approaches were reviewed. Descriptive statistics were performed. Results: In total, thirty-eight patients with suspected SWN were identified (median age 20 years, range 6–25; 32% female). NF2-related SWN was the most common diagnosis (31/38, 82%; de novo: 24/31 (77%) and familial: 7/31 (23%)), followed by LZTR1-SWN (n = 1) and SWN-NOS/NEC (n = 2). A total of four patients (asymptomatic LZTR1 carriers (n = 2) and possible SWN (n = 2)) did not fulfill diagnostic criteria based on craniospinal and whole-body MRI. Familial NF2-SWN demonstrated a trend toward earlier presentation (median 5 vs. 8 years; p = 0.12). Visual manifestations occurred at a younger age than hearing loss (median 8 vs. 16 years; p = 0.053). Imaging burden was high (median 23 MRI/patient (range: 1–60). Bilateral vestibular schwannomas were nearly universal (30/31, 97%). Familial disease demonstrated a trend toward increased cranial meningiomas (86% vs. 54%; p = 0.20), while peripheral schwannomas (43% vs. 67%; p = 0.38) and ependymomas (14% vs. 42%; p = 0.37) were less frequent compared with de novo disease. Operative and non-operative management was documented in 65% (20/31) each. Conclusions: NF2-related SWN is the predominant subtype in a pediatric and AYA patient population and was associated with substantial early tumor burden at a tertiary specialty NF center.

This series reports 3 unrelated individuals with features of neurofibromatosis type 1 (NF1) and/or schwannomatosis (SWN) in whom variants of uncertain significance (VUSs) were resolved through RNA testing and tissue analysis, highlighting the clinical impact of these tests. Each patient's genetic testing identified a VUS that could have explained their clinical presentation. Because diagnostic criteria were not met, we performed VUS resolution. For patient 1, we conducted tissue analysis and RNA-based Sanger sequencing. For patients 2 and 3, RNA-based Sanger sequencing was pursued. Tissue analysis and RNA testing reclassified the NF1 c.8050 + 93A>T VUS in patient 1 as pathogenic, confirming diagnosis of NF1. RNA testing of the NF2 c.448-5T>C VUS in patient 2 reclassified the variant as likely benign, ruling out diagnosis of germline neurofibromatosis type 2 (NF2). RNA testing of the SPRED1 c.377-13T>A VUS in patient 3 reclassified the variant as likely benign, ruling out diagnosis of germline Legius syndrome. Because diagnostic criteria for NF1 and SWN include genetic testing, resolving VUSs in those who do not meet criteria is crucial for clinical care. In this article, we report 3 cases in which RNA testing and tissue analysis clarified pathogenicity of VUSs, thereby affecting clinical care, and in one case providing a definitive diagnosis.