Genetics of Rolandic Epilepsy

罗兰迪克癫痫的遗传学

基本信息

批准号：
7364144
负责人：
DAVID A. GREENBERG
金额：
$ 47.83万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-24 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7364144
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

项目摘要

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.

描述（由申请人提供）：这项研究的目的是找到Rolandic癫痫（RE）的基因，这是复杂遗传遗传的发展局灶性癫痫。 RE是最常见的童年癫痫病，经常与特定的神经心理缺陷（NPDS）相关，这种观察结果并未通过治疗临床医生或教师而广泛理解。 NPD以及亚临床的脑电图性状也存在于RE患者的兄弟姐妹中，这表明RE是由几个具有重大影响的基因引起的，这种情况是链接和关联分析是理想的情况。我们建议使用链接分析来识别RE和NPD的敏感性基因座，并使用现代分子方法和关联分析来查明和鉴定这些基因座的疾病基因。该提案的三个具体目的是：（1）从至少100个具有典型的RE概率的家庭中收集详细的临床，脑电图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和专家小组来分类案件；（2）执行全基因组链接分析屏幕以识别RE的敏感性基因座。我们将使用链接分析测试：i）RE +/- eeg性状和NPD是同一基因型的表现； ii）RE的亚型，基于昼夜模式或癫痫发作频率，代表遗传异质形式； iii）大的，受影响的重生与核科有不同的继承； iv）re链接到特发性概括或局灶性癫痫的候选基因座；（3）在这些敏感性基因座上识别易于重复的基因和特异性突变，这有助于临床，治疗和认知结果的表达。我们将主要使用重组分析，致密SNP映射，单倍型重建和DNA测序进行精确的基因映射和突变检测。由于其发病率很高且目前未知的病因，因此找到RE基因很重要。更重要的是，与RE相关的NPD的原因，人口发生率和预后尚不清楚。我们可以从我们独特的宝贵资源中使用基因型 - 表型相关性来改善患者护理和计划早期干预。此外，这项研究的遗传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。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A neurocognitive endophenotype associated with rolandic epilepsy.

DOI：
10.1111/j.1528-1167.2011.03371.x
发表时间：
2012-04
期刊：
Epilepsia
影响因子：
5.6
作者：
Smith AB;Kavros PM;Clarke T;Dorta NJ;Tremont G;Pal DK
通讯作者：
Pal DK

Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4).

DOI：
10.1038/ejhg.2008.267
发表时间：
2009-09
期刊：
European journal of human genetics : EJHG
影响因子：
0
作者：
通讯作者：

Decreased functional connectivity within a language subnetwork in benign epilepsy with centrotemporal spikes.

DOI：
10.1002/epi4.12051
发表时间：
2017-06
期刊：
Epilepsia open
影响因子：
3
作者：
McGinnity CJ;Smith AB;Yaakub SN;Weidenbach Gerbase S;Gammerman A;Tyson AL;Bell TK;Elmasri M;Barker GJ;Richardson MP;Pal DK
通讯作者：
Pal DK

A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy.

DOI：
10.1002/acn3.320
发表时间：
2016-07
期刊：
Annals of clinical and translational neurology
影响因子：
5.3
作者：
Panjwani N;Wilson MD;Addis L;Crosbie J;Wirrell E;Auvin S;Caraballo RH;Kinali M;McCormick D;Oren C;Taylor J;Trounce J;Clarke T;Akman CI;Kugler SL;Mandelbaum DE;McGoldrick P;Wolf SM;Arnold P;Schachar R;Pal DK;Strug LJ
通讯作者：
Strug LJ

Risk factors for reading disability in families with rolandic epilepsy.

罗兰癫痫家族阅读障碍的危险因素。

DOI：
10.1016/j.yebeh.2015.10.016
发表时间：
2015
期刊：
Epilepsy & behavior : E&B
影响因子：
0
作者：
Vega,YaizaHernández;Smith,Anna;Cockerill,Hannah;Tang,Shan;Agirre-Arrizubieta,Zaloa;Goyal,Sushma;Pina,Marisa;Akman,CigdemI;Jolleff,Nicola;McGinnity,Colm;Gomez,Kumudini;Gupta,Rajesh;Hughes,Elaine;Jackman,John;McCormick,David;
通讯作者：