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Title: Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy
Austin Authors: Rudolf, Gabrielle;Lesca, Gaetan;Mehrjouy, Mana M;Labalme, Audrey;Salmi, Manal;Bache, Iben;Bruneau, Nadine;Pendziwiat, Manuela;Fluss, Joel;de Bellescize, Julitta;Scholly, Julia;Møller, Rikke S;Craiu, Dana;Tommerup, Niels;Valenti-Hirsch, Maria Paola;Schluth-Bolard, Caroline;Sloan-Béna, Frédérique;Helbig, Katherine L;Weckhuysen, Sarah;Edery, Patrick;Coulbaut, Safia;Abbas, Mohamed;Scheffer, Ingrid E ;Tang, Sha;Myers, Candace T;Stamberger, Hannah;Carvill, Gemma L;Shinde, Deepali N;Mefford, Heather C;Neagu, Elena;Huether, Robert;Lu, Hsiao-Mei;Dica, Alice;Cohen, Julie S;Iliescu, Catrinel;Pomeran, Cristina;Rubenstein, James;Helbig, Ingo;Sanlaville, Damien;Hirsch, Edouard;Szepetowski, Pierre
Affiliation: Austin Health, Heidelberg, Victoria, Australia
IGBMC, CNRS UMR7104, INSERM U964, Strasbourg University, Strasbourg, France
Federation of Translational Medicine, Strasbourg, France
Department of Neurology, Strasbourg University Hospital, Strasbourg, France
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
Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark
INSERM U901, Marseille, France
UMR S901, Aix-Marseille University, Marseille, France
Mediterranean Institute of Neurobiology (INMED), Marseille, France
Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
Department of Neuropediatrics, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany
Pediatric Neurology, Child and Adolescent Department, Geneva University Hospitals, Geneva, Switzerland
Epilepsy, Sleep and Pediatric Neurophysiology Department, Lyon University Hospitals, Lyon, France
Danish Epilepsy Centre, Dianalund, Denmark
Institute for Regional Health Research, University of Southern Denmark, Odense, Denmark
"Carol Davila" University of Medicine Bucharest, Department of Clinical Neurosciences (No.6), Pediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania
Department of Medical Genetics, University Hospitals of Geneva, Geneva, Switzerland
Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA
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
UCB-Pharma, Colombes, France
The Florey Institute of Neuroscience and Mental Health, the University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Victoria, Australia
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA
Human Genetics Laboratory, "Mina Minovici" National Institute of Forensic Medicine, Bucharest, Romania
Department of Bioinformatics, Ambry Genetics, Aliso Viejo, CA, USA
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
Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
Issue Date: 29-Jun-2016
Date: 2016-06-29
Publication information: European Journal of Human Genetics 2016; online first: 29 June
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.
DOI: 10.1038/ejhg.2016.80
ORCID: 0000-0002-2311-2174
Journal: European Journal of Human Genetics
PubMed URL:
Type: Journal Article
Appears in Collections:Journal articles

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