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
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DOI：
10.1038/ejhg.2016.80
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发表时间：
2016-12-01
影响因子：
5.2
通讯作者：
Szepetowski, Pierre
中科院分区：
文献类型：
--
作者：
Rudolf, Gabrielle;Lesca, Gaetan;Szepetowski, Pierre
遗传性全身性癫痫（GGE），以前称为特发性全身性癫痫，是癫痫的最常见形式，被认为具有主要的遗传病因。GGE的临床特征为失神、肌阵挛或全身强直阵挛发作，脑电图表现为双侧同步对称棘波放电。尽管有很强的遗传性，但全身性癫痫的遗传基础在很大程度上仍然难以捉摸。然而，最近的进展，在遗传技术已经导致了许多基因和基因组缺陷的各种类型的癫痫在过去几年中的鉴定。在本研究中，我们进行了全外显子组测序在一个家庭与GGE符合眼睑肌阵挛与缺席的诊断。我们发现了一个无意义的变体（C。196C>T/p。（Arg 66 *）），其编码β维甲酸相关孤儿核受体（ROR β），在四个受影响的家庭成员。此外，两个新生变异体（c.218T>C/p.（Leu73Pro）; c. 1249_1251delACG/p.（Thr417del））。我们还发现了两个从头缺失患者的行为和认知障碍和癫痫：一个52 kb的微缺失涉及外显子5-10的RORB和一个更大的9 q21微缺失。此外，我们确定了一名智力残疾和平衡易位的患者，其中一个断点截断RORB，并完善了最近报道的RORB缺失患者的表型。我们的数据支持RORB基因变异体/CNV在神经发育障碍包括癫痫，特别是在以失神发作为主的全身性癫痫中的作用。
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 (ROR beta), 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.