Eva-Katharina Willimsky 1, Anna Munzig 2, Karin Mayer 2, Saskia Biskup 3, Angela Abicht 4, Konstanze Hoertnagel 2, Hubertus von Voss 2, Hanns-Georg Klein 2, Imma Rost 2, Line H G Larsen 5, Hanns Atli Dahl 5, Hannes Hoelz 1, Celina von Stuelpnagel 1 6, Ingo Borggraefe 1 7
Introduction: Next generation sequencing (NGS) with customized gene panels is a helpful tool to identify monogenic epilepsy syndromes. The number of genes tested within a customized panel may vary greatly. The aim of the present study was to compare the diagnostic yield of small (<25 kb) and large (>25 kb) customized epilepsy panels.
Methods: This retrospective cohort study investigated data of 190 patients of 18 years or younger, with the diagnosis of an epilepsy of unknown etiology who underwent NGS using customized gene panels. Small (<25 kb) and large (>25 kb) panels were compared regarding the distribution of benign/likely benign and pathogenic/likely pathogenic variants and variants of unclear significance. In addition, differences of the diagnostic yield with respect to epilepsy severity, i.e., developmental and epileptic encephalopathy [DEE] vs. non-DEE, were analyzed.
Results: The diagnostic yield defined as pathogenic or likely pathogenic variants in large panels was significantly increased (29% [n = 14/48] vs. 13% [n = 18/142], p = 0.0198) compared with smaller panels. In non-DEE patients the increase of the diagnostic yield in large panels was significant(35% n = 6/17 vs. 13% n = 12/94, p = 0.0378), which was not true for DEE patients.
Discussion: This study indicates that large panels are superior for pediatric patients with epilepsy forms without encephalopathy (non-DEE). For patients suffering from DEE small panels of a maximum of 10 genes seem to be sufficient. The proportion of unclear findings increases with rising panel sizes.
Conclusion: Customized epilepsy panels of >25 kb compared with smaller panels show a significant higher diagnostic yield in patients with epilepsy especially in non-DEE patients.
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Conflict of interest statement
- Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics Department of Pediatrics, Ludwig-Maximilians University of Munich, Dr. von Hauner Children’s Hospital, Munich, Germany.
- Center of Human Genetics and Laboratory Diagnostics, Martinsried, Germany.
- CeGaT GmbH, Tübingen, Germany.
- Medical Genetics Center-MGZ, Munich, Germany.
- Amplexa Genetics, Odense, Denmark.
- Paracelsus Medical University, Salzburg, Austria.
- Comprehensive Epilepsy Center (Pediatric section), Ludwig-Maximilians University of Munich, Munich, Germany.