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 - Moller, 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

PY - 2016/12

Y1 - 2016/12

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.

U2 - 10.1038/ejhg.2016.80

DO - 10.1038/ejhg.2016.80

M3 - Journal article

C2 - 27352968

VL - 24

SP - 1761

EP - 1770

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

IS - 12

ER -