Genetics of Rolandic Epilepsy

描述(申请人提供)：这项研究的目标是找到罗兰迪克癫痫(RE)的基因，这是一种复杂遗传的发育性局灶性癫痫。RE是儿童最常见的癫痫，经常与特定的神经心理缺陷(NPD)有关，这一观察结果并未得到临床医生或教师的广泛重视。在RE患者的同胞中也发现了NPD和亚临床EEG特征，这表明RE是由几个主效基因引起的，这种情况下的连锁和关联分析是理想的。我们建议使用连锁分析来确定RE和NPD的易感基因座，并使用现代分子方法和关联分析来定位和识别这些基因座上的疾病基因。 该提案的三个具体目标是：(1)收集至少100个具有典型RE先证者的家庭的详细临床、脑电和神经心理学数据和DNA样本。我们将使用严格的资格标准和专家小组对病例进行细分；(2)进行全基因组连锁分析筛查，以确定RE的易感基因座。我们将使用连锁分析检验假设：i)RE/-EEG特征和NPD是同一基因型的表现；ii)基于日间模式或癫痫发作频率的RE亚型代表遗传异质性形式；iii)大型、密集受累的RE家系与核心家庭中发现的RE具有不同的遗传；iv)RE与特发性全身性或局灶性癫痫的候选基因连锁；(3)识别这些易感基因和这些易感基因座上的特定突变易导致RE，并有助于临床、治疗和认知结果的表达。我们将主要通过重组分析、密集SNP定位、单倍型重建和DNA测序来进行精确的基因定位和突变检测。 由于其发病率高且目前病因不明，寻找RE基因具有重要意义。更重要的是，与RE相关的NPD的病因、人群发病率和预后尚不清楚。我们可以从我们独特的宝贵的分子诊断工具资源中利用基因-表型相关性来改善患者护理并计划早期干预。此外，这项研究的基因发现将刺激相关的严重特发性局灶性儿童期癫痫和神经发育生物学的发现。

DESCRIPTION (provided by applicant): The goal of this research is to find the genes underlying Rolandic epilepsy (RE), a developmental focal epilepsy of complex genetic inheritance. RE is the most common epilepsy of childhood and is frequently associated with specific neuropsychological deficits (NPDs), an observation that is not widely appreciated by treating clinicians or by teachers. The NPDs, as well as a subclinical EEG trait, are also found in siblings of RE patients, suggesting RE is caused by a few genes of major effect, a situation for which linkage and association analysis are ideal. We propose to use linkage analysis to identify susceptibility loci for RE and NPDs, and use modern molecular methods and association analysis to pinpoint and identify disease genes at these loci. The three specific aims of the proposal are: (1) to collect detailed clinical, EEG and neuropsychological data and DNA samples from at least 100 families with a typical RE proband. We will use stringent eligibility criteria, and an expert panel to subclassify cases; (2) to perform a genome-wide linkage analysis screen to identify susceptibility loci for RE. We will test, using linkage analysis, the hypotheses that: i) the RE+/-EEG trait and NPDs are manifestations of the same genotype; ii) subtypes of RE, based on diurnal pattern or seizure frequency, represent genetically heterogeneous forms; iii) large, densely affected RE pedigrees have different inheritance from RE found in nuclear families; iv) RE is linked to candidate loci for idiopathic generalized or focal epilepsies; (3) Identify genes and specific mutations at these susceptibility loci that predispose to RE, and that contribute to the expression of clinical, treatment and cognitive outcomes. We will perform precise gene mapping and mutation detection principally using recombination analysis, dense SNP mapping, haplotype reconstruction and DNA sequencing. Finding RE genes is important because of its high incidence and currently unknown etiology. More importantly, the cause, population incidence, and prognosis of NPDs associated with RE is unknown. We can use genotype-phenotype correlations from our uniquely valuable resource for molecular diagnostic tools to improve patient care and to plan early intervention. Furthermore, genetic discoveries from this research will stimulate discoveries in related severe idiopathic focal childhood epilepsies and neurodevelopmental biology.