Genetics of Familial Epilepsy Syndromes

描述（由申请人提供）：癫痫影响大约百分之一的人口和200名儿童中的一名。癫痫综合征与已证实或可能的遗传原因大大有助于癫痫的原因，特别是在儿童中。在过去的半个世纪里，人们越来越认识到遗传因素在癫痫易感个体中起着重要作用。传统的方法连锁分析的家庭与明确定义的癫痫综合征已成功地确定基因负责这些综合征。迄今为止，这些基因中的大多数编码离子通道亚基，并提供了一个解释只有一小部分癫痫。我们假设，通过研究显性和隐性遗传的癫痫家族形式，我们将发现新的基因和新的过程，在发育中的大脑中为癫痫奠定基础。这一发现将加深我们对癫痫重要的发育过程和途径的理解，也可能为癫痫患者的合理药物治疗确定新的方法。我们将首先进行严格的表型方法，以个人诊断和家族性癫痫综合征的家庭中的个人进行分类。我们将使用全基因组遗传变异性标记（短串联重复序列多态性和单核苷酸多态性）来分析疾病状态和基因组位点之间的连锁，我们将进一步分析与位置克隆和高通量测序相关的区域，以确定这些家族中的特定基因突变。一旦实现了这一点，我们将筛选其他家庭和散发的个人与相同的癫痫表型的突变，在这些基因。候选人是一名经过委员会认证的儿童神经学家，并接受过额外的临床神经生理学/儿科EEG培训。她将在波士顿儿童医院的Christopher沃尔什博士的监督下进行这项研究，他是神经遗传学领域的著名专家，在脑畸形的遗传学方面具有丰富的临床和研究经验，并与Ruth Wellman博士共同指导，Ruth Wellman博士是癫痫遗传学领域的先驱，他开发了现在被接受为癫痫遗传学研究标准的表型方法。除了这些导师的联合培训外，候选人还将参加癫痫表型组基因组项目，并接受来自癫痫遗传学知名国家专家组的额外培训。她在培训期间获得的经验和技能将为临床神经科学研究的独立职业生涯奠定基础。 公共卫生相关性：癫痫是一种常见疾病，大约每一百人中就有一人受到影响。虽然癫痫的病因多种多样，但遗传学在许多人的癫痫发展中起着重要作用，并可能影响一个家庭中的几个人。该项目的目标是通过研究家族性癫痫的遗传学，更深入地了解癫痫的根本原因。

DESCRIPTION (provided by applicant): Epilepsy affects approximately one percent of the population and one in 200 children. Epilepsy syndromes with proven or likely genetic cause contribute substantially to the causes of epilepsy, especially in children. Over the last half century, there has been increasing recognition that genetic factors play an important role in predisposing individuals to epilepsy. The traditional approach of linkage analysis in families with well-defined epilepsy syndromes has been successful in identifying the genes responsible for some of these syndromes. To date, most of these genes encode ion channel subunits and provide an explanation for only a small proportion of epilepsy. We hypothesize that by studying familial forms of epilepsy with both dominant and recessive inheritance, we will discover novel genes and novel processes that set the stage for epilepsy in the developing brain. Such discovery will deepen our understanding of the developmental processes and pathways important in epilepsy and may also identify novel approaches to rational pharmacological treatment for patients with epilepsy. We will first perform rigorous phenotyping methods to classify individuals in families with individual diagnoses and familial epilepsy syndromes. We will use genome-wide markers of genetic variability (short tandem repeat polymorphisms and single nucleotide polymorphisms) to perform analyses of linkage between disease status and genomic loci, and we will further analyze the regions with evidence of linkage with positional cloning and high-throughput sequencing to identify specific genetic mutations in these families. Once this is achieved, we will screen other families and sporadic individuals with the same epilepsy phenotypes for mutations in these genes. The candidate is a board-certified child neurologist with additional clinical neurophysiology/pediatric EEG training. She will perform this research at Children's Hospital Boston under the supervision of Dr. Christopher Walsh, a renowned expert in the field of neurogenetics with extensive clinical and research experience in the genetics of brain malformations, with co-mentorship from Dr. Ruth Ottman, a pioneer in the field of epilepsy genetics who has developed the phenotyping methodologies now accepted as standard for epilepsy genetics research. In addition to the combined training under these mentors, the candidate will also participate in the Epilepsy Phenome Genome Project and receive additional training from a renowned group of national experts in epilepsy genetics. The experience and skills she will garner during this training period will set the stage for an independent career in clinical neuroscience research. PUBLIC HEALTH RELEVANCE: Epilepsy is a common condition, affecting approximately one in one hundred people. While the causes of epilepsy are varied, genetics play an important role in the development of epilepsy in many individuals and may affect several individuals in a family. The goal of this project is to gain deeper insight into the fundamental causes of epilepsy by studying the genetics of familial forms of epilepsy.