Genetics of Rolandic Epilepsy

罗兰迪克癫痫的遗传学

• 批准号: 7497199
• 负责人: DEB K PAL
• 金额: $ 4.98万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-24 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497199
• 关键词: 15q14; Adolescent; Affect; Arousal; Attention; Benign; Biological; Biology; Blood specimen; Childhood; Chromosome Mapping; Clinic; Clinical; Clinical Treatment; Cognitive; Complex; DNA; DNA Sequence; Data; Data Collection; Development; Diagnostic; Disease; Early Intervention; Electroencephalography; Eligibility Determination; Epilepsy; Etiology; Family; Family history of; Frequencies; Funding; Gene Mutation; Generalized Epilepsy; Genes; Genetic; Genetic Heterogeneity; Genetic Models; Genetic Recombination; Genome; Genotype; Goals; Haplotypes; Heterogeneity; Human; Incidence; Interview; Ion Channel; Lead; Learning; Link; Maps; Methods; Modeling; Molecular; Mutation; Mutation Detection; Nuclear Family; Numbers; Outcome; Partial Epilepsies; Patient Care; Patients; Pattern; Penetrance; Phenotype; Population; Predictive Value; Predisposition; Probability; Process; Recording of previous events; Reporting; Research; Research Proposals; Resources; Rolandic Epilepsy; Sampling; Seizures; Sensory Receptors; Siblings; Single Nucleotide Polymorphism Map; Source; Speed; Subgroup; Susceptibility Gene; Testing; base; density; family structure; gene discovery; genetic linkage analysis; genetic pedigree; genome-wide linkage; improved; neuropsychological; outcome forecast; proband; reconstruction; repository; response; teacher; tool; trait

IThe 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.

本研究的目的是寻找Rolandic癫痫（RE）的相关基因， 复杂遗传性癫痫RE是儿童最常见的癫痫， 与特定的神经心理缺陷（NPD）相关，这一观察结果并未得到广泛认可， 治疗临床医生或教师。NPD以及亚临床EEG特征也存在于 RE患者，这表明RE是由几个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的易感基因座， NPD，并使用现代分子方法和关联分析来精确定位和识别疾病基因 在这些地方。 该提案的三个具体目标是：（1）收集详细的临床、脑电图和神经心理学数据 和至少100个具有典型RE先证者的家庭的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选， 确定RE易感基因座。我们将使用连锁分析来测试以下假设：i）RE+/-EEG 性状和NPD是相同基因型的表现; ii）RE的亚型，基于昼夜模式或 癫痫发作频率，代表遗传异质性形式; iii）大的、密集受累的RE家系具有 与核心家族中发现的RE不同的遗传; iv）RE与特发性 全身性或局灶性癫痫;（3）确定这些易感基因座的基因和特定突变， 易患RE，并有助于临床、治疗和认知结果的表达。我们将 进行精确的基因定位和突变检测，主要使用重组分析，密集SNP 作图、单体型重建和DNA测序。 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 利用我们独特的有价值的分子诊断工具资源中的基因型-表型相关性， 改善病人护理和计划早期干预。此外，这项研究的基因发现将 刺激了相关严重特发性局灶性儿童癫痫和神经发育生物学的发现。