2. Academic Validation
  3. Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

  • Eur J Hum Genet. 2016 Dec;24(12):1761-1770. doi: 10.1038/ejhg.2016.80.
Gabrielle Rudolf 1 2 3,  Gaetan Lesca 4 5 6,  Mana M Mehrjouy 7,  Audrey Labalme 4,  Manal Salmi 8 9 10,  Iben Bache 7 11,  Nadine Bruneau 8 9 10,  Manuela Pendziwiat 12,  Joel Fluss 13,  Julitta de Bellescize 14,  Julia Scholly 3,  Rikke S Møller 15 16,  Dana Craiu 17,  Niels Tommerup 7,  Maria Paola Valenti-Hirsch 3,  Caroline Schluth-Bolard 4 5 6,  Frédérique Sloan-Béna 18,  Katherine L Helbig 19,  Sarah Weckhuysen 20 21 22,  Patrick Edery 4 5 6,  Safia Coulbaut 23,  Mohamed Abbas 23,  Ingrid E Scheffer 24,  Sha Tang 19,  Candace T Myers 25,  Hannah Stamberger 20 21 22,  Gemma L Carvill 25,  Deepali N Shinde 19,  Heather C Mefford 25,  Elena Neagu 26,  Robert Huether 27,  Hsiao-Mei Lu 27,  Alice Dica 17,  Julie S Cohen 28,  Catrinel Iliescu 17,  Cristina Pomeran 17,  James Rubenstein 28 29,  Ingo Helbig 12 30,  Damien Sanlaville 4 5 6,  Edouard Hirsch 1 2 3,  Pierre Szepetowski 8 9 10
Affiliations

Affiliations

  • 1 IGBMC, CNRS UMR7104, INSERM U964, Strasbourg University, Strasbourg, France.
  • 2 Federation of Translational Medicine, Strasbourg, France.
  • 3 Department of Neurology, Strasbourg University Hospital, Strasbourg, France.
  • 4 Department of Genetics, Lyon University Hospitals, Lyon, France.
  • 5 Claude Bernard Lyon I University, Lyon, France.
  • 6 Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France.
  • 7 Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark.
  • 8 INSERM U901, Marseille, France.
  • 9 UMR S901, Aix-Marseille University, Marseille, France.
  • 10 Mediterranean Institute of Neurobiology (INMED), Marseille, France.
  • 11 Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
  • 12 Department of Neuropediatrics, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.
  • 13 Pediatric Neurology, Child and Adolescent Department, Geneva University Hospitals, Geneva, Switzerland.
  • 14 Epilepsy, Sleep and Pediatric Neurophysiology Department, Lyon University Hospitals, Lyon, France.
  • 15 Danish Epilepsy Centre, Dianalund, Denmark.
  • 16 Institute for Regional Health Research, University of Southern Denmark, Odense, Denmark.
  • 17 "Carol Davila" University of Medicine Bucharest, Department of Clinical Neurosciences (No.6), Pediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania.
  • 18 Department of Medical Genetics, University Hospitals of Geneva, Geneva, Switzerland.
  • 19 Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
  • 20 Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.
  • 21 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  • 22 Division of Neurology, University Hospital Antwerp (UZA), Antwerp, Belgium.
  • 23 UCB-Pharma, Colombes, France.
  • 24 Florey Institute, University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Australia.
  • 25 Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, USA.
  • 26 Human Genetics Laboratory, "Mina Minovici" National Institute of Forensic Medicine, Bucharest, Romania.
  • 27 Department of Bioinformatics, Ambry Genetics, Aliso Viejo, CA, USA.
  • 28 Department of Neurology and Developmental Medicine, Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
  • 29 Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 30 Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
PMID: 27352968 DOI: 10.1038/ejhg.2016.80
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.

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