Genetic Etiologies of Agenesis of the Corpus Callosum

描述(申请人提供)：在胎儿发育的第8周和第14周之间形成的胼胝体，是连接两个大脑半球的主要纤维束。据估计，胼胝体发育不全(ACC)的发生率为1：4,000活产。ACC患者可能有严重的发育障碍和癫痫，并可能有认知和行为障碍，如自闭症、强迫症或注意缺陷多动障碍。在药物未用药的精神分裂症患者中也一致地发现了颧骨异常，这表明了解ACC的原因可能对理解其他神经行为障碍具有广泛的意义。 ACC的遗传病因目前尚不清楚，但某些细胞遗传学位点在ACC患者中反复缺失，提示ACC基因位于这些基因座上，该基因缺失一个拷贝可引起ACC。流行病学数据表明，2%的受影响个体有ACC的一级亲属，这与许多ACC患者可能具有新生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是明显的；参与穹隆形成的基因的缺失经常会导致CMS中的多个路径缺陷，而杂合性缺失可能只会导致穹隆异常。 我们采取了一种全面的方法来研究至少200名ACC患者及其家属的临床、放射学和遗传学特征。我们已经开始使用基因组微阵列测试我们的队列中染色体拷贝数的变化。在前25名患者中，我们确定了三个与ACC相关的亚微观从头缺失，这表明高达20%的ACC患者可能发生从头缺失。我们假设，剩下的80%中的一些人将在这些间隔中的一个区间内包含ACC致病基因的失活点突变。根据这些发现和假设，我们建议为这笔赠款实现以下目标： 1.继续开发一个全面的数据库，其中包括最初200名膝盖骨发育不全/发育不全患者的临床、历史和放射学信息。 2.利用加州大学旧金山分校32,000个BAG微阵列对200例ACC患者进行研究，以缩小先前已确定的ACC染色体间隔，并确定新的ACC间隔。 3.鉴定候选ACC基因的失活突变，这些突变位于ACC相关的三个染色体区间：2q37.1、6q27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.