Abstract：
We aim to identify genetic markers associated with idiopathic hypersomnia, a disabling orphan central nervous system disorder of hypersomnolence that is still poorly understood. In our study, DNA was extracted from 79 unrelated patients diagnosed with idiopathic hypersomnia with long sleep time at the National Reference Center for Narcolepsy-France according to very stringent diagnostic criteria. Whole exome sequencing on the first 30 patients with idiopathic hypersomnia (25 females and 5 males) allowed the single nucleotide variants to be compared with a control population of 574 healthy subjects from the French Exome project database. We focused on the identification of genetic variants among 182 genes related to the regulation of sleep and circadian rhythm. Candidate variants obtained by exome sequencing analysis were then validated in a second sample of 49 patients with idiopathic hypersomnia (37 females and 12 males). Our study characterised seven variants from six genes significantly associated with idiopathic hypersomnia compared with controls. A targeted sequencing analysis of these seven variants on 49 other patients with idiopathic hypersomnia confirmed the relative over-representation of the A➔C variant of rs2859390, located in a potential splicing-site of PER3 gene. Our findings support a genetic predisposition and identify pathways involved in the pathogeny of idiopathic hypersomnia. A variant of the PER3 gene may predispose to idiopathic hypersomnia with long sleep time.
摘要：
我们的目的是确定与特发性睡眠过度相关的遗传标记，一种致残的孤儿中枢神经系统疾病，引起的嗜睡过度。在我们的研究中,根据非常严格的诊断标准，在法国国家发作性睡病参考中心，从79名被诊断为睡眠时间长的特发性睡眠过度的无关患者中提取DNA。前30名特发性睡眠过度症患者（25名女性和5名男性）的全外显子组测序允许将单核苷酸变体与来自法国外显子组项目数据库的574名健康受试者的对照群体进行比较。我们专注于鉴定182个与睡眠和昼夜节律调节相关的基因中的遗传变异。然后在49例特发性睡眠过度患者(37例女性和12例男性)的第二样本中验证通过外显子组测序分析获得的候选变体。我们的研究表征了与对照组相比与特发性睡眠过度显着相关的六个基因的七个变体。对其他49例特发性睡眠过度症患者的这7种变异体进行靶向测序分析，证实了rs2859390的C变异体相对过度表达，该变异体位于PER3基因的潜在剪接位点。我们的发现支持遗传易感性，并确定了特发性睡眠过度的病因中涉及的途径。PER3基因的变体可能会导致睡眠时间长的特发性睡眠过度。
