Genetics of Rolandic Epilepsy

描述（由申请人提供）：本研究的目的是寻找罗兰德癫痫（RE）的潜在基因，这是一种复杂遗传的发育性局灶性癫痫。RE是儿童期最常见的癫痫，通常与特定的神经心理缺陷（NPD）相关，这一观察结果并未得到治疗临床医生或教师的广泛认可。在RE患者的兄弟姐妹中也发现了NPD以及亚临床EEG特征，这表明RE是由少数主要影响基因引起的，这种情况下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的易感位点，并使用现代分子方法和关联分析来定位和确定这些位点上的疾病基因。 该计划的三个具体目标是：（1）从至少100个具有典型RE先证者的家庭中收集详细的临床、EEG和神经心理学数据以及DNA样本。我们将使用严格的资格标准，并由专家小组对病例进行细分;（2）进行全基因组连锁分析筛选，以确定RE的易感基因位点。我们将使用连锁分析来检验以下假设：i）RE +/-EEG性状和NPD是相同基因型的表现; ii）基于昼夜模式或发作频率的RE亚型代表遗传异质性形式; iii）大的、密集受累的RE家系与核心家族中发现的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座连锁;（3）鉴定易患RE的这些易感基因座上的基因和特定突变，以及有助于临床、治疗和认知结果的表达。我们将主要使用重组分析、密集SNP作图、单体型重建和DNA测序进行精确的基因定位和突变检测。 由于RE发病率高，目前病因不明，因此寻找RE基因很重要。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。我们可以利用基因型-表型相关性，从我们独特的宝贵资源的分子诊断工具，以改善病人的护理和计划早期干预。此外，这项研究的遗传学发现将刺激相关的严重特发性局灶性儿童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.