Molecular Genetics of Kleine-Levin Syndrome

克莱恩-莱文综合征的分子遗传学

• 批准号: 7628459
• 负责人: Emmanuel J Mignot
• 金额: $ 36.28万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7628459
• 关键词: Accounting; Adolescence; Affect; Alleles; Ashkenazim; Behavior; Behavioral; Candidate Disease Gene; Case Series; Case Study; Child; Childhood; Classification; Clinical; Collaborations; Computer Simulation; Country; DNA; Data; Desire for food; Development; Disease; Environmental Risk Factor; Europe; Family; Founder Effect; Functional disorder; Genes; Genetic; Genetic Predisposition to Disease; Goals; Human; Hyperphagia; Impaired cognition; Israel; Kleine-Levin Syndrome; Lead; Literature; Maps; Molecular Genetics; Mutation; Nature; Neuraxis; Orphan; Parents; Patients; Play; Population; Predisposition; Prevalence; Principal Investigator; Publishing; Questionnaires; Rare Diseases; Recruitment Activity; Reporting; Research; Research Personnel; Sampling; Scanning; Single Nucleotide Polymorphism; Sleep; Susceptibility Gene; United States; Variant; base; density; effective therapy; follow-up; follower of religion Jewish; genetic analysis; genome wide association study; insight; neuropsychiatry; novel; proband; programs; sleep regulation

DESCRIPTION (provided by applicant): Kleine-Levin Syndrome (KLS) is an orphan neuropsychiatric disorder, typically starting in childhood or adolescence. Its primary manifestation is a periodic hypersomnia (dramatic increases in sleep amounts) of central nervous system origin. These bouts of hypersomnia are also associated with cognitive disturbances and behavioral abnormalities such as hyperphagia, irritability and hypersexuality. Systematic research on the cause of this disease is inexistent, and is urgently needed due to the disabling nature of the disease and the lack of effective treatments. KLS has traditionally been considered an exceptionally rare disease, with fewer than 200 cases reported worldwide over the past 50 years. It now appears to be more common than previously expected. We have identified and characterized over 100 additional cases by active recruitment in the United States, Europe and Israel. The cause of this disease is unknown, but likely involves a major gene. KLS may be disproportionately frequent in the Jewish population, as the largest case series has been reported in this country, accounting for nearly one sixth of all patients reported worldwide. Our recent data from the United States also indicates increased ascertainment of KLS in Ashkenazi Jews, suggesting a genetic founder effect. Results of our recruitment further support the action of genetic factors, as we identified 5 familial cases among our 104 probands (4.8%), extending on case reports of multiplex families published in the literature over the last 40 years. Based on the above and due to the fact that it would be difficult to gather enough multiplex families to conduct traditional linkage studies, we propose to conduct a genome wide association study in 200 trios to identify a major KLS genetic susceptibility locus. A sub-analysis will be performed on 40 Jewish trios to take advantage of the potential founder effect. We will pursue regions of association through fine mapping and in silico analysis of gene content. Finally, we will identify and characterize candidate genes within the critical regions and identify variants in KLS patients. Identification of a Kleine-Levin Syndrome susceptibility locus will help to unravel the pathophysiology of this intriguing disease. This may also lead to novel insights in the control of sleep, appetite and other instinctual behaviors, with potential applications in other periodic neuropsychiatric disorders.

描述（由申请人提供）：克莱恩·莱文综合征（KLS）是一种孤儿神经精神疾病，通常从儿童或青春期开始。它的主要表现是中枢神经系统起源的周期性高血压（睡眠量的急剧增加）。这些高血压症的回合也与认知障碍和行为异常有关，例如脾气暴躁，易怒和性交。关于这种疾病原因的系统研究是没有存在的，由于疾病的残疾性质和缺乏有效的治疗方法，因此迫切需要。传统上，KLS被认为是一种异常罕见的疾病，在过去的50年中，全球报告的病例少于200例。现在，它似乎比以前预期的更为普遍。我们通过在美国，欧洲和以色列的积极招募来确定并表征了100多个案例。这种疾病的原因尚不清楚，但可能涉及主要基因。在犹太人口中，KLS可能过于频繁，因为该国报告了最大的病例系列，占全世界所有患者的近六分之一。我们最近来自美国的数据还表明，阿什肯纳兹犹太人的KLS确定性增加，这表明遗传创始人效应。我们招募的结果进一步支持了遗传因素的作用，因为我们确定了104个概率中的5例家族病例（4.8％），并扩展了过去40年中文献中发表的多重家族的病例报告。基于上述内容，并且由于很难收集足够多的多重家族来进行传统的连锁研究，因此我们建议在200个三重奏中进行基因组广泛的关联研究，以识别主要的KLS遗传易感性基因座。将对40个犹太三重奏进行亚分析，以利用潜在的创始人效应。我们将通过精细的映射和基因含量分析来追求关联区域。最后，我们将识别并表征关键区域内的候选基因，并确定KLS患者的变体。鉴定克莱因湖综合征易感性基因座将有助于揭示这种有趣的疾病的病理生理学。这也可能导致对睡眠，食欲和其他本能行为的控制的新见解，并在其他周期性神经精神疾病中使用了潜在的应用。