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

艾卡迪综合征的基因发现：胼胝体发育不全的特例

• 批准号: 7448757
• 负责人: Elliott Sherr
• 金额: $ 20.27万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7448757
• 关键词: Affect; Aicardi' s syndrome; Autistic Disorder; Behavior; Birth; Brain; Brain Diseases; Candidate Disease Gene; Cerebral hemisphere; Cerebrum; Characteristics; Child; Choroid Plexus Papilloma; Clinical; Cognitive; Collaborations; Coloboma; Complex; Copy Number Polymorphism; Corpus Callosum; Custom; Cyst; DNA; DNA Sequence; Data; Databases; Detection; Development; Developmental Disabilities; Disease; Disruption; Elements; Embryo; Epilepsy; Evaluation; Event; Eye; Eye Development; Family; Female; Gene Expression; Genes; Genome; Genomics; Gestational Age; Grant; Image; Impairment; In Situ Hybridization; Incidence; Individual; Infantile spasms; Inherited; Lead; Longevity; Mental Retardation; Microgyria; Microphthalmos; Microsatellite Repeats; Microscopic; Mothers; Mus; Mutation; Mutation Analysis; Neurons; Numbers; Oligonucleotide Probes; Optic Disk; Outcome; Patients; Pattern; Phase; Phenotype; Polymerase Chain Reaction; Public Health; Publishing; Range; Resolution; Retinal; Role; Scanning; Seizures; Syndrome; System; Testing; X Chromosome; X Inactivation; base; brain disorder diagnosis; brain malformation; chromosome mutation; clinical phenotype; cohort; comparative genomic hybridization; density; design; developmental disease; gene discovery; male; malformation; periventricular heterotopia

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.

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，同一基因中的较少的渗透突变可以导致认知和行为障碍，而没有结构变化，这表明这些基因在大脑发育和功能中具有广泛适用的作用。我们预计，发现与这些脑畸形有关的基因将对我们理解智力低下、自闭症和癫痫产生直接而重要的影响，这将成为靶向治疗的第一步。我们建议将该补助金集中在阿卡迪综合征（AS）上。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、脉络膜视网膜陷窝和婴儿痉挛。这些患者还经常有其他脑畸形，包括多脑回，皮质下和脑室周围异位，大脑不对称，脉络丛乳头状瘤和囊肿，等等。只有女性和XXY（Klinefelter）男性受到影响，这种零星的疾病，从来没有发生在一个家庭两次（有一个例外）。这些研究结果表明，阿维尼翁迪综合征是由X染色体上的从头突变引起的。我们建议使用微阵列平台来搜索致病基因，该平台将扫描X染色体的DNA，寻找可能将我们指向阿维尼翁综合征基因的缺失或重复。我们还将通过候选基因的方法来研究AS的病因。此外，一旦基因被鉴定，许多发育障碍就会被发现具有更广泛的临床表型。我们计划利用这一潜在方面的AS测序新发现的AS基因在一个大的队列的个人与胼胝体发育不全，标志性的脑畸形的阿托迪综合征。 公共卫生关系：这一发现最终将对我们理解大脑如何发育以及大脑发育畸形患者如何发生癫痫发作产生广泛影响。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。