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dc.contributor.authorGorman, Kathleen M-
dc.contributor.authorMeyer, Esther-
dc.contributor.authorGrozeva, Detelina-
dc.contributor.authorSpinelli, Egidio-
dc.contributor.authorMcTague, Amy-
dc.contributor.authorSanchis-Juan, Alba-
dc.contributor.authorCarss, Keren J-
dc.contributor.authorBryant, Emily-
dc.contributor.authorReich, Adi-
dc.contributor.authorSchneider, Amy L-
dc.contributor.authorPressler, Ronit M-
dc.contributor.authorSimpson, Michael A-
dc.contributor.authorDebelle, Geoff D-
dc.contributor.authorWassmer, Evangeline-
dc.contributor.authorMorton, Jenny-
dc.contributor.authorSieciechowicz, Diana-
dc.contributor.authorJan-Kamsteeg, Eric-
dc.contributor.authorPaciorkowski, Alex R-
dc.contributor.authorKing, Mary D-
dc.contributor.authorCross, J Helen-
dc.contributor.authorPoduri, Annapurna-
dc.contributor.authorMefford, Heather C-
dc.contributor.authorScheffer, Ingrid E-
dc.contributor.authorHaack, Tobias B-
dc.contributor.authorMcCullagh, Gary-
dc.contributor.authorMillichap, John J-
dc.contributor.authorCarvill, Gemma L-
dc.contributor.authorClayton-Smith, Jill-
dc.contributor.authorMaher, Eamonn R-
dc.contributor.authorRaymond, F Lucy-
dc.contributor.authorKurian, Manju A-
dc.identifier.citationAmerican journal of human genetics 2019; online first: 10 April-
dc.description.abstractThe occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.-
dc.subjectdevelopmental and epileptic encephalopathy (DEE)-
dc.titleBi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.-
dc.typeJournal Article-
dc.identifier.journaltitleAmerican journal of human genetics-
dc.identifier.affiliationDepartment of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK.en
dc.identifier.affiliationDivision of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester M13 9NT, UKen
dc.identifier.affiliationDepartment of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UKen
dc.identifier.affiliationMolecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UKen
dc.identifier.affiliationDepartment of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UKen
dc.identifier.affiliationDepartment of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, UKen
dc.identifier.affiliationDivision of Psychological Medicine and Clinical Neuroscience, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UKen
dc.identifier.affiliationEpilepsy Center, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USAen
dc.identifier.affiliationDepartment of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0PT, UKen
dc.identifier.affiliationNIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ UKen
dc.identifier.affiliationDivision of Genetics, Birth Defects and Metabolism, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USAen
dc.identifier.affiliationGeneDx, Gaithersburg, MD 20877, USAen
dc.identifier.affiliationEpilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australiaen
dc.identifier.affiliationDepartment of Clinical Neurophysiology, Great Ormond Street Hospital, London WC1N 3JH, UKen
dc.identifier.affiliationClinical Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UKen
dc.identifier.affiliationDivision of Genetics and Molecular Medicine, King's College, London WC2R 2LS, UKen
dc.identifier.affiliationDepartment of General Paediatrics, Birmingham Children's Hospital, Birmingham B4 6NH, UKen
dc.identifier.affiliationDepartment of Paediatric Neurology, Birmingham Children's Hospital, Birmingham B4 6NH, UKen
dc.identifier.affiliationWest Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's NHS Foundation Trust, Birmingham B15 2TG, UKen
dc.identifier.affiliationDepartments of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USAen
dc.identifier.affiliationDepartment of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, Netherlandsen
dc.identifier.affiliationDepartment of Neurology, Pediatrics and Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USAen
dc.identifier.affiliationDepartment of Neurology and Clinical Neurophysiology, Children's University Hospital, Temple Street, Dublin DO1 YC67, Irelanden
dc.identifier.affiliationAcademic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 4, Irelanden
dc.identifier.affiliationEpilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USAen
dc.identifier.affiliationDepartment of Neurology, Harvard Medical School, Boston, MA 02115, USAen
dc.identifier.affiliationDivision of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USAen
dc.identifier.affiliationFlorey Institute and Murdoch Institute of Neuroscience and Mental Health, Parkville, 3052, VIC, Australiaen
dc.identifier.affiliationDepartment of Paediatrics, Royal Children's Hospital, University of Melbourne, Parkville, 3052, VIC, Australiaen
dc.identifier.affiliationInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen 72706, Germanyen
dc.identifier.affiliationDepartment of Neurology, Royal Manchester Children's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UKen
dc.identifier.affiliationDDD Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UKen
dc.identifier.affiliationUK10K, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UKen
dc.identifier.affiliationKen and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USAen
dc.identifier.affiliationManchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals, NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UKen
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