Gene Discovery in Aicardi Syndrome: A Special Case of Callosal Agenesis

描述（由申请人提供）：脑畸形是严重发育障碍和癫痫发作的重要原因。在许多情况下，同一基因中渗透性较低的突变可以导致认知和行为障碍，而不会发生结构变化，这表明这些基因在大脑发育和功能中具有广泛的适用作用。我们预计，发现与这些大脑畸形有关的基因将对我们对智力迟钝、自闭症和癫痫的理解产生直接而重要的影响，这将是迈向靶向治疗的第一步。我们建议将这笔拨款重点用于阿卡迪综合征（AS）。这是一种独特的大脑和眼睛发育障碍，其标志性体征是胼胝体发育不全，绒毛膜视网膜陷窝和婴儿痉挛。这些患者还经常有其他脑畸形，包括多小回畸形、皮质下和心室周围异位、大脑不对称、脉络膜丛乳头状瘤和囊肿等。只有女性和XXY （Klinefelter）男性受到影响，这种散发性疾病从未在一个家庭中发生两次（只有一个例外）。这些发现表明，Aicardi综合征是由X染色体上的新生突变引起的。我们建议使用微阵列平台搜索致病基因，该平台将扫描X染色体上的DNA，寻找可能指向Aicardi综合征基因的缺失或重复。我们还将通过寻找候选基因的方法来研究AS的病因。此外，一旦确定了该基因，许多发育障碍被发现具有更广泛的临床表型。我们计划通过对大量胼胝体发育不全（Aicardi综合征的标志性脑畸形）个体中新发现的AS基因进行测序，利用AS的这一潜在方面。公共卫生相关性：这一发现将最终对我们理解大脑如何发育以及癫痫如何在大脑发育畸形患者中发生产生广泛的影响。这也将对我们理解和诊断受影响儿童和孕妇大脑发育障碍的能力产生重要影响。

DESCRIPTION (provided by applicant): Brain malformations are a significant cause of severe developmental disability and seizures. In many cases, less penetrant mutations in the same gene can lead to cognitive and behavior impairment without structural changes, suggesting a broadly applicable role for these genes in brain development and function. We anticipate that discovery of genes involved in these brain malformations will have direct and important implications on our understanding of mental retardation, autism and epilepsy and that this will serve as this first step toward targeted therapies. We propose to focus this grant on Aicardi syndrome (AS). This is a unique disorder of brain and eye development for which the hallmark signs are agenesis of the corpus callosum, chorioretinal lacunae and infantile spasms. These patients also frequently have other brain malformations that include polymicrogyria, subcortical and periventricular heterotopia, cerebral asymmetry, choroid plexus papillomas and cysts, amongst others. Only females and XXY (Klinefelter) males are affected and this sporadid disorder, never occurring twice in one family (with one exception). These constellation of findings suggest that Aicardi syndrome is caused by a de novo mutation on the X chromosome. We propose to search for the causative gene using a microarray platform that will scan DNA from the X chromosome looking for deletions or duplications which may point us to the Aicardi syndrome gene. We also will pursue the cause of AS by pursuing a candidate gene approach. Moreover, many developmental disorders are found to have a broader clinical phenotype once the gene is identified. We plan to capitalize on this potential aspect of AS by sequencing the newly identified AS gene in a large cohort of individuals with agenesis of the corpus callosum, the hallmark cerebral malformation in Aicardi syndrome. PUBLIC HEALTH RELEVANCE: This discovery will ultimately have broad implications on our understanding of how the brain develops and how seizures occur in patients with malformations of brain development. This will also have important implications for our ability to understand and diagnose disorders of brain development both in affected children and in expectant mothers.