title: Extending the phenotypic spectrum of RBFOX1 deletions: Sporadic focal epilepsy.
abstract: Partial deletions of the RBFOX1 gene encoding the neuronal splicing regulator have been reported in a range of neurodevelopmental diseases including idiopathic/genetic generalized epilepsy (IGE/GGE), childhood focal epilepsy, and self-limited childhood benign epilepsy with centrotemporal spikes (BECTS, rolandic epilepsy), and autism. The protein regulates alternative splicing of many neuronal transcripts involved in the homeostatic control of neuronal excitability. Herein, we examined whether structural deletions affecting RBFOX1 exons confer susceptibility to common forms of juvenile and adult focal epilepsy syndromes. We screened 807 unrelated patients with sporadic focal epilepsy, and we identified seven hemizygous exonic RBFOX1 deletions in patients with sporadic focal epilepsy (0.9%) in comparison to one deletion found in 1,502 controls. The phenotypes of the patients carrying RBFOX1 deletions comprise magnetic resonance imaging (MRI)-negative epilepsy of unknown etiology with frontal and temporal origin (n = 5) and two patients with temporal lobe epilepsy with hippocampal sclerosis. The epilepsies were largely pharmacoresistant but not associated with intellectual disability. Our study extends the phenotypic spectrum of RBFOX1 deletions as a risk factor for focal epilepsy and suggests that exonic RBFOX1 deletions are involved in the broad spectrum of focal and generalized epilepsies.
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.|Department of Neuropediatrics, University Medical Center Giessen and Marburg, Giessen, Germany.|Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Lal
authors.affiliation: Department of Neuropathology, University of Bonn, Bonn, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Pernhorst
authors.affiliation: Department of Neurology, University of Marburg, Marburg, Germany.
authors.forename: Karl Martin
authors.initials: KM
authors.lastname: Klein
authors.affiliation: Department of Neurology, University of Marburg, Marburg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Reif
authors.affiliation: C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Tozzi
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Toliat
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Winterer
authors.affiliation: Department of Neuropediatrics, University Medical Center Giessen and Marburg, Giessen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Neubauer
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Department of Neurology, University of Marburg, Marburg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Rosenow
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Becker
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.affiliation: Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, U.S.A.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts, U.S.A.|Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Mitja I
authors.initials: MI
authors.lastname: Kurki
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Division of Medical Genetics, University Hospital, Basel, Switzerland.|Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Department of Neuropathology, University of Bonn, Bonn, Germany.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Becker
authors.affiliation: C. Mondino National Neurological Institute, Pavia, Italy.|Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Perucca
authors.affiliation: Laboratory of Neurogenetics, Neuromuscular Disease Unit, Istituto G. Gaslini, Genova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Weber
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004828:Epilepsies, Partial / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D010641:Phenotype; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins
keywords: Copy number variation; Cryptogenic; Genetic; Idiopathic; Lesional; Magnet resonance imaging negative