Holistic Exome-Based Genetic Testing in Adults With Epilepsy

Martin Krenn; Matias Wagner; Karin Trimmel; Silvia Bonelli; Jakob Rath; Judith Jud; Michelle Schwarz; Ivan Milenkovic; Rosa Weng; Johannes Koren; Christoph Baumgartner; Melanie Brugger; Theresa Brunet; Elisabeth Graf; Juliane Winkelmann; Susanne Aull-Watschinger; Fritz Zimprich; Ekaterina Pataraia

doi:10.1212/NXG.0000000000200260

Holistic Exome-Based Genetic Testing in Adults With Epilepsy

Neurol Genet. 2025 Apr 17;11(3):e200260. doi: 10.1212/NXG.0000000000200260. eCollection 2025 Jun.

Authors

Martin Krenn^{1

2}, Matias Wagner^{3

4}, Karin Trimmel^{1

2}, Silvia Bonelli^{1

2}, Jakob Rath^{1

2}, Judith Jud^{1

2}, Michelle Schwarz^{1

2}, Ivan Milenkovic^{1

2}, Rosa Weng^{1

2}, Johannes Koren^{5

6}, Christoph Baumgartner^{5

6}, Melanie Brugger^{3

7}, Theresa Brunet^{3

8}, Elisabeth Graf³, Juliane Winkelmann^{3

4}, Susanne Aull-Watschinger^{1

2}, Fritz Zimprich^{1

2}, Ekaterina Pataraia^{1

2}

Affiliations

¹ Department of Neurology, Medical University of Vienna, Austria.
² Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, Austria.
³ Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Germany.
⁴ Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.
⁵ Karl Landsteiner Institute for Clinical Epilepsy Research and Cognitive Neurology, Vienna, Austria.
⁶ Department of Neurology, Clinic Hietzing, Vienna, Austria.
⁷ Department of Obstetrics and Gynecology, Klinikum Rechts der Isar, Technical University of Munich, Germany; and.
⁸ Department of Pediatric Neurology and Developmental Medicine and Ludwig Maximilians University Center for Children with Medical Complexity, Dr. von Hauner Children's Hospital, Ludwig Maximilians University Hospital, Ludwig Maximilians University, Munich, Germany.

Abstract

Background and objectives: Exome sequencing (ES) is increasingly used in the diagnostic workup of epilepsies. While its utility has been extensively demonstrated in children, its role in adults remains to be defined. In this study, we evaluate the outcomes of a holistic exome-based approach in adults with epilepsy.

Methods: We included 106 adults with epilepsy and a presumed genetic etiology between January 2015 and December 2023 at the Medical University of Vienna, Austria. Diagnostic ES, including copy number variation (CNV) and mitochondrial analyses, was performed. We report on diagnostic outcomes, phenotype expansions, and research findings. Furthermore, we compared the diagnostic outcomes with 3 comprehensive gene panels.

Results: In our cohort, the diagnostic yield was 30.2%, outperforming all 3 simulated gene panels. A developmental and epileptic encephalopathy phenotype was associated with receiving a genetic diagnosis. Overall, 27 distinct molecular etiologies were identified. Eight patients had pathogenic CNVs, and 2 had mitochondrial DNA variants. Molecular diagnoses had potential clinical implications in 8 of 32 solved cases (25%), which were eventually exerted in 5 patients (15.6%). Tailored treatment changes were successfully applied in SCN1A-related epilepsy (discontinuation of sodium channel blockers) and GLUT1 deficiency (ketogenic diet). Three patients with mitochondrial diseases were referred for preventive screening investigations after the genetic diagnosis. Our findings expand the clinical spectrum of 3 known epilepsy genes. In addition, explorative variant prioritization identified heterozygous truncating variants in CLASP1 in 2 unrelated patients with focal epilepsy, suggesting it as a candidate gene.

Discussion: Our study strongly supports the use of holistic genetic approaches, encompassing CNV and mitochondrial analyses, in adults with epilepsy. Similar to pediatric cohorts, results may inform clinical care. Moreover, we report on phenotype expansions and a candidate gene discovery.