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

Gabrielle Rudolf, Gaetan Lesca, Mana M. Mehrjouy, Audrey Labalme, Manal Salmi, Iben Bache, Nadine Bruneau, Manuela Pendziwiat, Joel Fluss, Julitta De Bellescize, Julia Scholly, Rikke S. Møller, Dana Craiu, Niels Tommerup, Maria Paola Valenti-Hirsch, Caroline Schluth-Bolard, Frédérique Sloan-Béna, Katherine L. Helbig, Sarah Weckhuysen, Patrick EderySafia Coulbaut, Mohamed Abbas, Ingrid E. Scheffer, Sha Tang, Candace T. Myers, Hannah Stamberger, Gemma L. Carvill, Deepali N. Shinde, Heather C. Mefford, Elena Neagu, Robert Huether, Hsiao Mei Lu, Alice Dica, Julie S. Cohen, Catrinel Iliescu, Cristina Pomeran, James Rubenstein, Ingo Helbig, Damien Sanlaville, Edouard Hirsch, Pierre Szepetowski

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1761-1770
Number of pages10
JournalEuropean Journal of Human Genetics
Issue number12
StatePublished - Dec 1 2016

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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