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
{"title":"成人癫痫患者的整体外显子组基因检测。","authors":"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","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objectives: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 <i>SCN1A</i>-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 <i>CLASP1</i> in 2 unrelated patients with focal epilepsy, suggesting it as a candidate gene.</p><p><strong>Discussion: </strong>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.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 3","pages":"e200260"},"PeriodicalIF":3.0000,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060788/pdf/","citationCount":"0","resultStr":"{\"title\":\"Holistic Exome-Based Genetic Testing in Adults With Epilepsy.\",\"authors\":\"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\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objectives: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 <i>SCN1A</i>-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 <i>CLASP1</i> in 2 unrelated patients with focal epilepsy, suggesting it as a candidate gene.</p><p><strong>Discussion: </strong>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. 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Holistic Exome-Based Genetic Testing in Adults With Epilepsy.
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.
期刊介绍：
Neurology: Genetics is an online open access journal publishing peer-reviewed reports in the field of neurogenetics. Original articles in all areas of neurogenetics will be published including rare and common genetic variation, genotype-phenotype correlations, outlier phenotypes as a result of mutations in known disease-genes, and genetic variations with a putative link to diseases. This will include studies reporting on genetic disease risk and pharmacogenomics. In addition, Neurology: Genetics will publish results of gene-based clinical trials (viral, ASO, etc.). Genetically engineered model systems are not a primary focus of Neurology: Genetics, but studies using model systems for treatment trials are welcome, including well-powered studies reporting negative results.
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