New strategies to identify the gene mutated in Aicardi syndrome

描述（由申请人提供）：该项目的最终目标是确定在Aparthodi综合征中突变的基因，Aparthodi综合征是一种罕见的神经发育障碍，几乎只影响女性，并与智力迟钝有关。它被认为是由从头X连锁显性杂合突变引起的。受影响的女孩目前有一个典型的三联体发育不全的胼胝体，严重的癫痫发作（婴儿痉挛症）和脉络膜视网膜陷窝。其他缺陷，包括神经元迁移，视神经和其他器官系统的异常往往存在。这表明，突变的基因在阿博迪综合征在正常发育中具有重要的复杂功能。表型的变异性比最初确定的要大，这可能部分是由于患者之间X染色体失活（XCI）模式的差异。此外，具有最复杂表型的一小部分患者可能具有影响一个以上基因功能的基因组缺失或重复。因为所有的阿卡迪综合征病例都是散发性的，所以不可能通过遗传连锁来定位携带突变基因的位点。对于这个研究项目，我们提出了三个具体的目标，以寻求其他新的策略来找到阿卡迪综合征基因。在具体目标1中，我们将更详细地描述表型，并研究大量患者DNA上的XCI模式，为该疾病的X连锁遗传提供进一步支持。在具体目标2中，我们将在基因组DNA微阵列上使用比较基因组杂交来筛选患者DNA中的微缺失或重复。在第三个具体目标中，我们将对X染色体上的候选基因进行突变分析，这些基因将根据其已知或推定的功能及其表达模式进行选择。为了选择这些基因，我们还将考虑在具有相似表型的条件下被破坏的分子途径，以及协调在Aparthodi综合征中受影响最大的器官系统发育的途径。至于其他罕见的神经发育障碍，发现阿维尼翁综合征基因不仅有利于诊断和治疗这种疾病，还将增加对指导大脑，眼睛和其他受影响器官系统发育的分子途径的了解。了解这些生物学过程将有助于发现，诊断和治疗许多发育障碍。这将改善儿童的健康。

DESCRIPTION (provided by applicant): The ultimate goal of this project is to identify the gene that is mutated in Aicardi syndrome, a rare neurodevelopment disorder that affects almost exclusively females and is associated with mental retardation. It is thought to be caused by de novo X-linked dominant heterozygous mutations. Affected girls present with a typical triad of agenesis of the corpus callosum, severe seizures (infantile spasms) and chorioretinal lacunae. Other defects, including abnormalities of neuronal migration, optic nerve and other organ systems are often present. This suggests that the gene mutated in Aicardi syndrome has important complex functions in normal development. There is more variability in the phenotype than was initially ascertained, which may in part result from differences in X chromosome inactivation (XCI) patterns between patients. In addition, a small subset of patients with the most complex phenotype may have a genomic deletion or duplication that affects the function of more than one gene. Because all cases of Aicardi syndrome are sporadic, genetic linkage to map the locus that harbors the mutated gene is not possible. For this research project we propose three specific aims to pursue other novel strategies to find the Aicardi syndrome gene. In specific aim 1, we will characterize the phenotype in more detail and study XCI patterns on a large number of patient DNAs to provide further support for the X-linked inheritance of the condition. In specific aim 2, we will use comparative genomic hybridization on genomic DNA micro arrays to screen for micro deletions or duplications in DNA from patients. In the third specific aim, we will perform mutation analysis of candidate genes on the X chromosome that will be selected based on their known or putative function and their expression pattern. To select these genes, we will also take into account the molecular pathways that are disrupted in conditions with similar phenotypes and the pathways that orchestrate the development of the organ systems most affected in Aicardi syndrome. As for other rare neurodevelopment disorders, finding the Aicardi syndrome gene will not only benefit diagnosis and treatment of this disorder, it will also increase knowledge on molecular pathways that guide development of the brain, eye and other affected organ systems. Understanding these biological processes will benefit discovery, diagnosis and treatment of many developmental disorders. This will improve the health of children.