Bianca Berghuis1, Carolien G F de Kovel2, Loretta van Iterson3, Robert J Lamberts4, Josemir W Sander5, Dick Lindhout6, Bobby P C Koeleman2. 1. Stichting Epilepsie Instellingen Nederland SEIN, Zwolle, The Netherlands. Electronic address: bberghuis@sein.nl. 2. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 3. Stichting Epilepsie Instellingen Nederland SEIN, Zwolle, The Netherlands; De Waterlelie School, Expertisecentrum voor Onderwijs en Epilepsie, Cruquius, The Netherlands. 4. Stichting Epilepsie Instellingen Nederland SEIN, Zwolle, The Netherlands. 5. Stichting Epilepsie Instellingen Nederland SEIN, Zwolle, The Netherlands; NIHR UCL Hospitals Biomedical Research Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom; Epilepsy Society, Chalfont St Peter SL9 0RJ, United Kingdom. 6. Stichting Epilepsie Instellingen Nederland SEIN, Zwolle, The Netherlands; Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Abstract
BACKGROUND: De novo SCN8A missense mutations have been identified as a rare dominant cause of epileptic encephalopathy. We described a person with epileptic encephalopathy associated with a mosaic deletion of the SCN8A gene. METHODS: Array comparative genome hybridization was used to identify chromosomal abnormalities. Next Generation Sequencing was used to screen for variants in known and candidate epilepsy genes. A single nucleotide polymorphism array was used to test whether the SCN8A variants were in cis or in trans. RESULTS: We identified a de novo mosaic deletion of exons 2-14 of SCN8A, and a rare maternally inherited missense variant on the other allele in a woman presenting with absence seizures, challenging behavior, intellectual disability and QRS-fragmentation on the ECG. We also found a variant in SCN5A. CONCLUSIONS: The combination of a rare missense variant with a de novo mosaic deletion of a large part of the SCN8A gene suggests that other possible mechanisms for SCN8A mutations may cause epilepsy; loss of function, genetic modifiers and cellular interference may play a role. This case expands the phenotype associated with SCN8A mutations, with absence epilepsy and regression in language and memory skills.
BACKGROUND: De novo SCN8A missense mutations have been identified as a rare dominant cause of epileptic encephalopathy. We described a person with epileptic encephalopathy associated with a mosaic deletion of the SCN8A gene. METHODS: Array comparative genome hybridization was used to identify chromosomal abnormalities. Next Generation Sequencing was used to screen for variants in known and candidate epilepsy genes. A single nucleotide polymorphism array was used to test whether the SCN8A variants were in cis or in trans. RESULTS: We identified a de novo mosaic deletion of exons 2-14 of SCN8A, and a rare maternally inherited missense variant on the other allele in a woman presenting with absence seizures, challenging behavior, intellectual disability and QRS-fragmentation on the ECG. We also found a variant in SCN5A. CONCLUSIONS: The combination of a rare missense variant with a de novo mosaic deletion of a large part of the SCN8A gene suggests that other possible mechanisms for SCN8A mutations may cause epilepsy; loss of function, genetic modifiers and cellular interference may play a role. This case expands the phenotype associated with SCN8A mutations, with absence epilepsy and regression in language and memory skills.
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