Genetic Etiologies of Agenesis of the Corpus Callosum

描述（由申请人提供）：胼胝体形成于胎儿发育的第8周到第14周之间，是连接两个大脑半球的主要纤维束。胼胝体（ACC）的发育估计发生率为1：4，000活产。患有ACC的患者可能具有显著的发育障碍和癫痫发作，并且可能具有认知和行为障碍，例如自闭症、强迫症或注意缺陷多动障碍。胼胝体异常也一直被发现在药物初治的精神分裂症患者，这表明，了解ACC的原因可能有广泛的意义，了解其他神经行为障碍。 ACC的遗传原因在很大程度上是未知的，然而，某些细胞遗传学位点在ACC患者中反复缺失，这表明ACC基因位于这些位点，缺失一个基因拷贝可以导致ACC. Epidemiological数据表明，2%的受影响的个体有一级亲属与ACC，与许多ACC患者可能有从头致病突变的可能性一致。ACC中基因剂量的这种作用在动物模型中也很明显;胼胝体形成中涉及的基因的缺失经常导致CMS中的多个寻路缺陷，而杂合缺失可能仅导致胼胝体异常。 我们已经采取了一种全面的方法来研究至少200例ACC患者及其家属的临床、影像学和遗传特征。我们已经开始使用基因组微阵列测试我们的队列的染色体拷贝数变化。在前25例患者中，我们发现了三个与ACC相关的亚显微从头缺失，这表明从头缺失可能发生在高达20%的ACC患者中。我们假设，剩余的80%中的一些将在这些间隔之一内包含的ACC致病基因中具有失活点突变。根据这些研究结果和假设，我们建议就这笔赠款实现以下目标： 1.继续开发一个关于最初200例胼胝体发育不全/发育不全患者的临床、历史和放射学信息的综合数据库。 2.为了缩小以前确定的ACC染色体间隔，并确定新的ACC间隔利用UCSF 32，000 BAG微阵列对200例ACC患者。 3.为了鉴定候选ACC基因中的失活突变，这些基因包含在三个ACC相关的染色体间隔中：2q37.1，6 q27和3q13.1。

DESCRIPTION (provided by applicant): The corpus callosum, formed between the 8th and 14th weeks of fetal development, is the principal fiber tract that connects the two cerebral hemispheres. Agenesis of the corpus callosum (ACC) has an estimated incidence of 1:4,000 live births. Patients with ACC can have significant developmental disability and seizures and may have cognitive and behavioral impairment such as autism, obsessive compulsive disorder or attention deficit hyperactivity disorder. Callosal anomalies have also been found consistently in drug-naive schizophrenic patients, suggesting that understanding the causes of ACC may have broad implications for understanding other neurobehavioral disorders. The genetic causes for ACC are largely unknown, however, certain cytogenetic loci are repeatedly deleted in ACC patients, suggesting that ACC genes reside in these loci and that missing one copy of the gene can cause ACC. Epidemiological data suggest that 2% of affected individuals have first-degree relatives with ACC, consistent with the possibility that many ACC patients may have de novo causative mutations. This role for gene dosage in ACC is also evident in animal models; deletion of genes involved in callosal formation frequently results in multiple pathfinding defects in the CMS, whereas heterozygous deletion may only result in callosal anomalies. We have undertaken a comprehensive approach to study the clinical, radiographic and genetic features of at least 200 ACC patients and their families. We have begun to test our cohort for chromosomal copy number changes using genomic microarrays. In the first 25 patients, we identified three submicroscopic de novo deletions that correlate with ACC, suggesting that de novo deletions may occur in up to 20% of ACC patients. We hypothesize that some of the remaining 80% will have inactivating point mutations in ACC causative genes contained within one of these intervals. In light of these findings and hypotheses, for this grant we propose to tackle the following Aims: 1. To continue to develop a comprehensive database of clinical, historical and radiologic information on an initial 200 patients with callosal agenesis/dysgenesis. 2. To narrow down previously identified ACC chromosomal intervals and to identify novel ACC intervals utilizing the UCSF 32,000 BAG microarray on 200 ACC patients. 3. To identify inactivating mutations in candidate ACC genes, which are contained in three ACC-associated chromosomal intervals: 2q37.1, 6q27 and 3q13.1.