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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：大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，同一基因中的渗透突变较少会导致认知和行为障碍而没有结构变化，这表明这些基因在脑发育和功能中的作用广泛适用。我们预计，发现这些大脑畸形所涉及的基因将对我们对智力低下，自闭症和癫痫的理解具有直接而重要的影响，这将是迈向靶向疗法的第一步。我们建议将此赠款集中在AICARDI综合征（AS）上。这是一种独特的大脑和眼睛发育障碍，标志性的迹象是call体，脉络膜结肠和婴儿痉挛的疾病。这些患者还经常发生其他脑畸形，包括多肌毛，皮质下和脑室杂质，大脑不对称，脉络膜丛乳头瘤和囊肿等。只有女性和XXY（Klinefelter）雄性受到影响，而这种散发性疾病在一个家庭中从未发生过两次（一个例外）。这些发现的星座表明，AICARDI综合征是由X染色体的从头突变引起的。我们建议使用微阵列平台搜索因果基因，该平台将从X染色体中扫描DNA，以寻找可能将我们指向AICARDI综合征基因的删除或重复。我们还将通过追求候选基因方法来追求AS的原因。此外，一旦鉴定出该基因，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患有Callosum callosum的人群（AICARDI综合征的Hallmark脑畸形）进行测序，利用AS的这一潜在方面。公共卫生相关性：这一发现最终将对我们对大脑发展方式以及脑发育畸形患者的癫痫发作的理解具有广泛的影响。这也将对我们理解和诊断受影响儿童和准妈妈的大脑发育障碍的能力具有重要意义。