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每200个儿童中就有一个。经证实或可能有遗传原因的癫痫综合征对癫痫的病因有很大贡献，特别是在儿童中。在过去的半个世纪里，人们越来越多地认识到遗传因素在使个人患癫痫方面发挥着重要作用。在具有明确定义的癫痫综合征的家族中，传统的连锁分析方法已经成功地识别了导致其中一些综合征的基因。到目前为止，这些基因中的大多数都编码离子通道亚基，并只为一小部分癫痫提供了解释。我们假设，通过研究同时具有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，为癫痫在发育中的大脑奠定基础。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找到新的途径。我们将首先执行严格的表型方法，对有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标记(短串联重复序列多态和单核苷酸多态)来分析疾病状态和基因组座位之间的连锁，并将进一步分析与位置克隆和高通量测序相关联的区域，以确定这些家族中特定的基因突变。一旦实现这一点，我们将筛查具有相同癫痫表型的其他家族和零星个体，以寻找这些基因的突变。应聘者是一名获得董事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在克里斯托弗·沃尔什博士的指导下进行这项研究，克里斯托弗·沃尔什博士是神经遗传学领域的著名专家，在脑畸形遗传学方面具有丰富的临床和研究经验，Ruth Ottman博士是癫痫遗传学领域的先驱，她开发了表型分析方法，目前已被公认为癫痫遗传学研究的标准。除了在这些导师的指导下进行的综合培训外，候选人还将参加癫痫表型基因组计划，并接受一个著名的国家癫痫遗传学专家小组的额外培训。她在这段培训期间将获得的经验和技能将为她在临床神经科学研究领域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，大约每百人中就有一人受到影响。虽然癫痫的原因多种多样，但遗传在许多人的癫痫发展中起着重要作用，可能会影响到一个家庭中的几个人。这个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.