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）：本研究的目标是找到 Rolandic 癫痫 (RE) 的基因，这是一种复杂遗传遗传的发育性局灶性癫痫。 RE 是儿童期最常见的癫痫症，通常与特定的神经心理缺陷 (NPD) 相关，但治疗临床医生或教师并未广泛认识到这一观察结果。 RE 患者的兄弟姐妹中也发现了 NPD 以及亚临床脑电图特征，这表明 RE 是由少数具有主要影响的基因引起的，对于这种情况，连锁和关联分析是理想的。我们建议使用连锁分析来识别 RE 和 NPD 的易感位点，并使用现代分子方法和关联分析来查明和识别这些位点的疾病基因。该提案的三个具体目标是：（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。我们将采用严格的资格标准，并由专家小组对案件进行细分； (2) 进行全基因组连锁分析筛选，以确定 RE 的易感位点。我们将使用连锁分析来测试以下假设： i) RE+/-EEG 特征和 NPD 是相同基因型的表现； ii) RE 亚型，基于昼夜模式或癫痫发作频率，代表遗传异质形式； iii) 大型、受影响严重的 RE 谱系与核心家族中发现的 RE 具有不同的遗传性； iv) RE 与特发性全身性或局灶性癫痫的候选基因座相关； (3) 识别这些易感位点上易患 RE 并有助于临床、治疗和认知结果表达的基因和特定突变。我们将主要利用重组分析、密集SNP作图、单倍型重建和DNA测序来进行精确的基因作图和突变检测。寻找 RE 基因非常重要，因为它的发病率很高且目前病因尚不清楚。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。我们可以利用分子诊断工具独特宝贵资源中的基因型-表型相关性来改善患者护理并规划早期干预。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：