TY - JOUR
T1 - Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy
AU - Rudolf, Gabrielle
AU - Lesca, Gaetan
AU - Mehrjouy, Mana M.
AU - Labalme, Audrey
AU - Salmi, Manal
AU - Bache, Iben
AU - Bruneau, Nadine
AU - Pendziwiat, Manuela
AU - Fluss, Joel
AU - De Bellescize, Julitta
AU - Scholly, Julia
AU - Møller, Rikke S.
AU - Craiu, Dana
AU - Tommerup, Niels
AU - Valenti-Hirsch, Maria Paola
AU - Schluth-Bolard, Caroline
AU - Sloan-Béna, Frédérique
AU - Helbig, Katherine L.
AU - Weckhuysen, Sarah
AU - Edery, Patrick
AU - Coulbaut, Safia
AU - Abbas, Mohamed
AU - Scheffer, Ingrid E.
AU - Tang, Sha
AU - Myers, Candace T.
AU - Stamberger, Hannah
AU - Carvill, Gemma L.
AU - Shinde, Deepali N.
AU - Mefford, Heather C.
AU - Neagu, Elena
AU - Huether, Robert
AU - Lu, Hsiao Mei
AU - Dica, Alice
AU - Cohen, Julie S.
AU - Iliescu, Catrinel
AU - Pomeran, Cristina
AU - Rubenstein, James
AU - Helbig, Ingo
AU - Sanlaville, Damien
AU - Hirsch, Edouard
AU - Szepetowski, Pierre
N1 - Funding Information:
We thank all the patients and families who participated in the study. We thank Professor Jamel Chelly for helpful discussion and comments and Raphaelle Lamy for expert technical assistance. Assistance from the Biological Resource Centre, Hospices Civils, Lyon, France and from the Banque de Génome, Hôpital de Brabois, Vandoeuvre-les-Nancy, France was greatly appreciated. We also thank Tine Deconinck and Tania Djémié for development and analysis of the MAQ assay. We also thank Dr Goedele Malfroid for helpful information for the patient EC-CAE300. This work was supported by a generous grant from UCB-Pharma France, by ANR (Agence Nationale de la Recherche) grant 'EPILAND' (ANR-2010-BLAN-1405 01) with EuroBiomed label, by the European Union Seventh Framework Programme FP7/2007-2013 under the project DESIRE (grant agreement no. 602531), by INSERM, by 'Young Hospital Researcher' 2007 grant from Hospices Civils de Lyon, by the Lundbeck Foundation (2013-14290), the UCPH Programme for Interdisciplinary Research (Global Genes, Local Concerns), and The Danish Council for Independent Research - Medical Sciences (4183-00482B).
Publisher Copyright:
© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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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U2 - 10.1038/ejhg.2016.80
DO - 10.1038/ejhg.2016.80
M3 - Article
C2 - 27352968
AN - SCOPUS:84976349143
SN - 1018-4813
VL - 24
SP - 1761
EP - 1770
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 12
ER -