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Krenn, M.* ; Wagner, M. ; Trimmel, K.* ; Bonelli, S.* ; Rath, J.* ; Jud, J.* ; Schwarz, M.* ; Milenkovic, I.* ; Weng, R.* ; Koren, J.* ; Baumgartner, C.* ; Brugger, M.* ; Brunet, T.* ; Graf, E.* ; Winkelmann, J. ; Aull-Watschinger, S.* ; Zimprich, F.* ; Pataraia, E.*

Holistic exome-based genetic testing in adults with epilepsy.

Neurol. Genet. 11:e200260 (2025)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Variants
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 2376-7839
e-ISSN 2376-7839
Zeitschrift Neurology Genetics
Quellenangaben Band: 11, Heft: 3, Seiten: , Artikelnummer: e200260 Supplement: ,
Verlag American Academy of Neurology
Verlagsort Minneapolis, Minn.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-503200-001
DOI 10.1212/NXG.0000000000200260
WOS ID 001484004300002
Scopus ID 105005068630
PubMed ID 40343077
Erfassungsdatum 2025-05-10
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