Clinical next generation sequencing in developmental and epileptic encephalopathies: Diagnostic relevance of data re-analysis and variants re-interpretation |
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| Affiliation: | 1. Neurogenetics Unit, Hospital JM Ramos Mejía, Buenos Aires, Argentina;2. Precision Medicine and Clinical Genomics Group, Translational Medicine Research Institute-CONICET, Faculty of Biomedical Sciences, Universidad Austral, Buenos Aires, Argentina;3. Paediatric Neurology Unit, Hospital Universitario Austral, Buenos Aires, Argentina;4. CETES, Instituto de Neurología Infanto-Juvenil, Córdoba, Argentina;5. Paediatric Neurology Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina;6. Genetic Unit, Hospital Aleman, Buenos Aires, Argentina;1. Department of Medical Sciences, University of Turin, Turin, Italy;2. Immunogenetics and Transplant Biology Service, Città della Salute e della Scienza University Hospital, Turin, Italy;3. Pediatric Nephrology Dialysis and Transplantation Unit, Città della Salute e della Scienza University Hospital, Turin, Italy;4. Department of Pediatrics, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy;1. Centre de Référence des Epilepsies Rares, Department of Paediatric Neurology, Hôpital Necker Enfants Malades, Inserm, U663, Paris, F-75015; University Paris Descartes, PRES Sorbonne Paris Cité, Paris, F-75005; CEA, Neurospin, 91190 Gif/Yvette, France;2. Department of Genetics, Inserm U781, Hôpital Necker Enfants Malades, Paris Descartes University, Imagine Institute, Paris, France;1. Laboratory of Molecular and Cellular Screening Processes (LPCMC), Center of Biotechnology of Sfax, University of Sfax, Tunisia;2. Medical Genetics Department, University Hedi Chaker Hospital of Sfax, Tunisia;3. Child Neurology Department, University Hedi Chaker Hospital of Sfax, Tunisia;4. Research Laboratory “Neuropédiatrie" LR19ES15, Sfax University, Tunisia;5. Radiology Department, Hedi Chaker University Hospital, University of Sfax, Sfax, Tunisia;6. Department of Ophthalmology, Habib Bourguiba Hospital, Sfax, Tunisia;7. Department of Otorhinolaryngology, University Habib Bourguiba Hospital of Sfax, Tunisia;8. Laboratory of Human Molecular Genetics, LR33ES99, Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia;9. Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah, United Arab Emirates;10. Human Genetics and Stem Cell Laboratory, Research Institute of Sciences and Engineering, University of Sharjah, Sharjah, United Arab Emirates;11. Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates;1. Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan;2. Department of Pediatrics, Toshima Hospital, Tokyo, Japan;3. Institute of Medical Genetics, Tokyo Women’s Medical University, Tokyo, Japan;4. Department of Pediatrics, Tokyo Women’s Medical University Yachiyo Medical Center, Yachiyo, Japan;1. Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan;2. Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Kanagawa, Japan;3. Department of Pediatric Neurology, MinamiKyushu Hospital, Kagoshima, Japan;4. Research Center for Children and Research Center for Rett syndrome, St. Mary’s Hospital, Fukuoka, Japan;1. Institute of Medical Genetics, Tokyo Women''s Medical University, Tokyo, Japan;2. Department of Medical Genetics, Osaka Women''s and Children''s Hospital, Osaka, Japan;3. School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia |
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| Abstract: | Developmental and epileptic encephalopathies (DEE) are complex pediatric epilepsies, in which heterogeneous pathogenic factors play an important role. Next-generation-sequencing based tools have shown excellent effectiveness. The constant increase in the number of new genotype-phenotype associations suggests the periodic need for re-interpretation and re-analysis of genetic studies without positive results. In this study, we report the diagnostic utility of targeted gene panel sequencing and whole exome sequencing in 55 Argentine subjects with DEE, focusing on the utility of re-interpretation and re-analysis of undetermined and negative genetic diagnoses. The new information in biomedical literature and databases was used for the re-interpretation. For re-analysis, sequencing data processing was repeated using updated bioinformatics tools.Initially, pathogenic variants were detected in 21 subjects (38%). After an average time of 29 months, 25% of the subjects without a genetic diagnosis were re-categorized as diagnosed. Finally, the overall diagnostic yield increased to 53% (29 subjects). In consequence of the re-interpretation and re-analysis, we identified novel variants in the genes: CHD2, COL4A1, FOXG1, GABRA1, GRIN2B, HNRNPU, KCNQ2, MECP2, PCDH19, SCN1A, SCN2A, SCN8A, SLC6A1, STXBP1 and WWOX. Our results expand the diagnostic yield of this subgroup of infantile and childhood seizures and demonstrate the importance of re-evaluation of genetic tests in subjects without an identified causative etiology. |
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| Keywords: | Variants of uncertain significance Targeted gene panel sequencing Whole exome sequencing Pediatric epilepsy Recessive epilepsy Re-interpretation |
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