Jonna Komulainen-Ebrahim1, John M Schreiber2, Salla M Kangas3, Katri Pylkäs4, Maria Suo-Palosaari5, Elisa Rahikkala6, Johanna Liinamaa7, Esa-Ville Immonen8, Ilmo Hassinen9, Päivi Myllynen10, Heikki Rantala11, Reetta Hinttala3, Johanna Uusimaa12. 1. PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Division of Pediatric Neurology, Oulu University Hospital, Oulu, Finland. Electronic address: jonna.komulainen-ebrahim@oulu.fi. 2. Epilepsy and Clinical Neurophysiology, Children's National Health System, Washington, DC, USA. 3. PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland. 4. Biocenter Oulu, University of Oulu, Oulu, Finland; Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland. 5. Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland; Department of Diagnostic Radiology, Oulu University Hospital, Oulu, Finland; Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland. 6. PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland; Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland. 7. PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland; Department of Ophthalmology, Oulu University Hospital, Oulu, Finland. 8. PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland; Nano and Molecular Systems Research Unit, University of Oulu, Oulu, Finland. 9. Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland. 10. Department of Clinical Chemistry, University of Oulu, Oulu, Finland; Nordlab Oulu, Oulu University Hospital, Oulu, Finland. 11. PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Division of Pediatric Neurology, Oulu University Hospital, Oulu, Finland. 12. PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Division of Pediatric Neurology, Oulu University Hospital, Oulu, Finland.
Abstract
PURPOSE: Next-generation sequencing (NGS) has made genetic testing of patients with epileptic encephalopathies easier - novel variants are discovered and new phenotypes described. Variants in the same gene - even the same variant - can cause different types of epilepsy and neurodevelopmental disorders. Our aim was to identify the genetic causes of epileptic encephalopathies in paediatric patients with complex phenotypes. METHODS: NGS was carried out for three patients with epileptic encephalopathies. Detailed clinical features, brain magnetic resonance imaging and electroencephalography were analysed. We searched the Human Gene Mutation Database for the published GABRG2 variants with clinical description of patients and composed a summary of the variants and their phenotypic features. RESULTS: We identified two novel de novo GABRG2 variants, p.P282T and p.S306F, with new phenotypes including neuroradiological evidence of neurodegeneration and epilepsy of infancy with migrating focal seizures (EIMFS). One patient carried previously reported p.P83S variant with autism spectrum disorder (ASD) phenotype that has not yet been described related to GABRG2 disorders and a more severe epilepsy phenotype than reported earlier. In all, the literature search yielded twenty-two articles describing 27 different variants that were divided into two categories: those with self-limiting epilepsies and febrile seizures and those with more severe drug-resistant epileptic encephalopathies. CONCLUSION: This study further expands the genotypic and phenotypic spectrum of epilepsies associated with GABRG2 variants. More knowledge is still needed about the influence of the environment, genetic background and other epilepsy susceptibility genes on the phenotype of the specific GABRG2 variants.
PURPOSE: Next-generation sequencing (NGS) has made genetic testing of patients with epileptic encephalopathies easier - novel variants are discovered and new phenotypes described. Variants in the same gene - even the same variant - can cause different types of epilepsy and neurodevelopmental disorders. Our aim was to identify the genetic causes of epileptic encephalopathies in paediatric patients with complex phenotypes. METHODS: NGS was carried out for three patients with epileptic encephalopathies. Detailed clinical features, brain magnetic resonance imaging and electroencephalography were analysed. We searched the Human Gene Mutation Database for the published GABRG2 variants with clinical description of patients and composed a summary of the variants and their phenotypic features. RESULTS: We identified two novel de novo GABRG2 variants, p.P282T and p.S306F, with new phenotypes including neuroradiological evidence of neurodegeneration and epilepsy of infancy with migrating focal seizures (EIMFS). One patient carried previously reported p.P83S variant with autism spectrum disorder (ASD) phenotype that has not yet been described related to GABRG2 disorders and a more severe epilepsy phenotype than reported earlier. In all, the literature search yielded twenty-two articles describing 27 different variants that were divided into two categories: those with self-limiting epilepsies and febrile seizures and those with more severe drug-resistant epileptic encephalopathies. CONCLUSION: This study further expands the genotypic and phenotypic spectrum of epilepsies associated with GABRG2 variants. More knowledge is still needed about the influence of the environment, genetic background and other epilepsy susceptibility genes on the phenotype of the specific GABRG2 variants.
Authors: Tiong Yang Tan; Jiří Sedmík; Mark P Fitzgerald; Rivka Sukenik Halevy; Liam P Keegan; Ingo Helbig; Lina Basel-Salmon; Lior Cohen; Rachel Straussberg; Wendy K Chung; Mayada Helal; Reza Maroofian; Henry Houlden; Jane Juusola; Simon Sadedin; Lynn Pais; Katherine B Howell; Susan M White; John Christodoulou; Mary A O'Connell Journal: Am J Hum Genet Date: 2020-03-26 Impact factor: 11.025