title: Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy.
abstract: Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C>T/p.(Arg66*)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORβ), in four affected family members. In addition, two de novo variants (c.218T>C/p.(Leu73Pro); c.1249_1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.
authors.affiliation: IGBMC, CNRS UMR7104, INSERM U964, Strasbourg University, Strasbourg, France.|Federation of Translational Medicine, Strasbourg, France.|Department of Neurology, Strasbourg University Hospital, Strasbourg, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Rudolf
authors.affiliation: Department of Genetics, Lyon University Hospitals, Lyon, France.|Claude Bernard Lyon I University, Lyon, France.|Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France.
authors.forename: Gaetan
authors.initials: G
authors.lastname: Lesca
authors.affiliation: Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mana M
authors.initials: MM
authors.lastname: Mehrjouy
authors.affiliation: Department of Genetics, Lyon University Hospitals, Lyon, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Labalme
authors.affiliation: INSERM U901, Marseille, France.|UMR S901, Aix-Marseille University, Marseille, France.|Mediterranean Institute of Neurobiology (INMED), Marseille, France.
authors.forename: Manal
authors.initials: M
authors.lastname: Salmi
authors.affiliation: Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark.|Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Iben
authors.initials: I
authors.lastname: Bache
authors.affiliation: INSERM U901, Marseille, France.|UMR S901, Aix-Marseille University, Marseille, France.|Mediterranean Institute of Neurobiology (INMED), Marseille, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Bruneau
authors.affiliation: Department of Neuropediatrics, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pendziwiat
authors.affiliation: Pediatric Neurology, Child and Adolescent Department, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Joel
authors.initials: J
authors.lastname: Fluss
authors.affiliation: Epilepsy, Sleep and Pediatric Neurophysiology Department, Lyon University Hospitals, Lyon, France.
authors.forename: Julitta
authors.initials: J
authors.lastname: de Bellescize
authors.affiliation: Department of Neurology, Strasbourg University Hospital, Strasbourg, France.
authors.forename: Julia
authors.initials: J
authors.lastname: Scholly
authors.affiliation: Danish Epilepsy Centre, Dianalund, Denmark.|Institute for Regional Health Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.affiliation: "Carol Davila" University of Medicine Bucharest, Department of Clinical Neurosciences (No.6), Pediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania.
authors.forename: Dana
authors.initials: D
authors.lastname: Craiu
authors.affiliation: Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.affiliation: Department of Neurology, Strasbourg University Hospital, Strasbourg, France.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Valenti-Hirsch
authors.affiliation: Department of Genetics, Lyon University Hospitals, Lyon, France.|Claude Bernard Lyon I University, Lyon, France.|Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schluth-Bolard
authors.affiliation: Department of Medical Genetics, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Sloan-Béna
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Helbig
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Division of Neurology, University Hospital Antwerp (UZA), Antwerp, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.affiliation: Department of Genetics, Lyon University Hospitals, Lyon, France.|Claude Bernard Lyon I University, Lyon, France.|Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Edery
authors.affiliation: UCB-Pharma, Colombes, France.
authors.forename: Safia
authors.initials: S
authors.lastname: Coulbaut
authors.affiliation: UCB-Pharma, Colombes, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abbas
authors.affiliation: Florey Institute, University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Tang
authors.affiliation: Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, USA.
authors.forename: Candace T
authors.initials: CT
authors.lastname: Myers
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Division of Neurology, University Hospital Antwerp (UZA), Antwerp, Belgium.
authors.forename: Hannah
authors.initials: H
authors.lastname: Stamberger
authors.affiliation: Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, USA.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Carvill
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
authors.forename: Deepali N
authors.initials: DN
authors.lastname: Shinde
authors.affiliation: Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, USA.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.affiliation: Human Genetics Laboratory, "Mina Minovici" National Institute of Forensic Medicine, Bucharest, Romania.
authors.forename: Elena
authors.initials: E
authors.lastname: Neagu
authors.affiliation: Department of Bioinformatics, Ambry Genetics, Aliso Viejo, CA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Huether
authors.affiliation: Department of Bioinformatics, Ambry Genetics, Aliso Viejo, CA, USA.
authors.forename: Hsiao-Mei
authors.initials: HM
authors.lastname: Lu
authors.affiliation: "Carol Davila" University of Medicine Bucharest, Department of Clinical Neurosciences (No.6), Pediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania.
authors.forename: Alice
authors.initials: A
authors.lastname: Dica
authors.affiliation: Department of Neurology and Developmental Medicine, Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Cohen
authors.affiliation: "Carol Davila" University of Medicine Bucharest, Department of Clinical Neurosciences (No.6), Pediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania.
authors.forename: Catrinel
authors.initials: C
authors.lastname: Iliescu
authors.affiliation: "Carol Davila" University of Medicine Bucharest, Department of Clinical Neurosciences (No.6), Pediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania.
authors.forename: Cristina
authors.initials: C
authors.lastname: Pomeran
authors.affiliation: Department of Neurology and Developmental Medicine, Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.|Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: James
authors.initials: J
authors.lastname: Rubenstein
authors.affiliation: Department of Neuropediatrics, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.|Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.affiliation: Department of Genetics, Lyon University Hospitals, Lyon, France.|Claude Bernard Lyon I University, Lyon, France.|Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Sanlaville
authors.affiliation: IGBMC, CNRS UMR7104, INSERM U964, Strasbourg University, Strasbourg, France.|Federation of Translational Medicine, Strasbourg, France.|Department of Neurology, Strasbourg University Hospital, Strasbourg, France.
authors.forename: Edouard
authors.initials: E
authors.lastname: Hirsch
authors.affiliation: INSERM U901, Marseille, France.|UMR S901, Aix-Marseille University, Marseille, France.|Mediterranean Institute of Neurobiology (INMED), Marseille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Szepetowski
mesh_terms: D000328:Adult; D002648:Child; D056905:Chromosome Breakpoints; D002872:Chromosome Deletion; D018389:Codon, Nonsense; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D004829:Epilepsy, Generalized / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2 / Q000235:genetics*; D010375:Pedigree; D013577:Syndrome; D014178:Translocation, Genetic
chemical_list: D018389:Codon, Nonsense; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2; C539740:RORB protein, human