Genetics of Familial Epilepsy Syndromes

描述（由申请人提供）：癫痫影响大约1%的人口，每200名儿童中就有1名癫痫患者。经证实或可能有遗传原因的癫痫综合征在很大程度上导致癫痫，特别是儿童癫痫。在过去的半个世纪里，人们越来越认识到遗传因素在个体易患癫痫方面起着重要作用。传统的方法连锁分析的家庭与明确定义的癫痫综合征已经成功地确定了一些这些综合征负责的基因。迄今为止，这些基因大多编码离子通道亚基，只能解释一小部分癫痫。我们假设，通过研究家族性癫痫的显性和隐性遗传，我们将发现新的基因和新的过程，为癫痫在发育中的大脑中奠定基础。这一发现将加深我们对癫痫的发育过程和重要途径的理解，也可能为癫痫患者的合理药物治疗找到新的方法。我们将首先执行严格的表型方法来分类个体的家庭个体诊断和家族性癫痫综合征。我们将使用遗传变异的全基因组标记（短串联重复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联系，我们将进一步分析有联系证据的区域，使用定位克隆和高通量测序来确定这些家庭中的特定基因突变。一旦实现这一目标，我们将筛查具有相同癫痫表型的其他家族和散发性个体，以寻找这些基因的突变。候选人是一名委员会认证的儿童神经科医生，接受过额外的临床神经生理学/儿童脑电图培训。她将在波士顿儿童医院接受Christopher Walsh博士的指导，Christopher Walsh博士是神经遗传学领域的知名专家，在脑畸形遗传学方面拥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，他开发的表型方法现已被接受为癫痫遗传学研究的标准。除了这些导师的联合培训外，候选人还将参加癫痫表型基因组计划，并接受著名的国家癫痫遗传学专家小组的额外培训。她将在此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。

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.