Modeling the Human Neuronal Phenotype of the Schizophrenia-Associated 3q29 deletion

项目摘要/摘要 与一系列神经精神表型有关，包括轻度至中度智力残疾， 自闭症、焦虑症和精神分裂症的风险增加40倍。尽管3q29缺失很少见(约1/30,000 出生)，其神经精神表型的高风险加上其相对较低的复杂性(22个基因在 删除间隔)，使其成为分子解剖的理想选择。3q29引起的神经细胞表型研究 缺失可能揭示了精神分裂症、自闭症和/或 智力残疾。我们建议从4个维度评估缺失携带者的行为特征：认知 能力、焦虑症、自闭症谱系，以及精神病或前驱症状的存在。我们还将采集血液 从缺失携带者和相关对照中提取样本，并将这些材料存入罗格斯大学细胞和 供研究界使用的DNA存储库(RUCDR)。最后，我们将模拟人类神经元 使用来自精神病患者缺失携带者的iPSC系进行表型分析。这将是第一个人类 3q29缺失的神经元模型。了解因缺失而中断的特定生物过程 在这个区间的22个基因中，可能为了解关键的神经发育过程提供了一个分子窗口 与神经精神病学表型有关。所有的表型数据、分子数据和细胞系都将迅速 通过ndar、dbGaP(dbgap.ncbi.nlm.nih.gov)和NIMH资源库和基因组学资源共享 (nimhgentics.org)。

Project Summary/Abstract 3q29 deletion syndrome is caused by a recurrent typically de novo 1.6 Mb heterozygous deletion and is associated with a range of neuropsychiatric phenotypes, including mild to moderate intellectual disability, autism, anxiety, and a 40-fold increased risk for schizophrenia. Although the 3q29 deletion is rare (~1 in 30,000 births), its high risk for neuropsychiatric phenotypes coupled with its relatively low complexity (22 genes in the deletion interval) make it ideal for molecular dissection. Investigating the neuronal phenotype caused by 3q29 deletion may reveal a core neurodevelopmental process that is disrupted in schizophrenia, autism, and/or intellectual disability. We propose to assess deletion carriers for behavioral traits along 4 dimensions: cognitive ability, anxiety, autism spectrum, and presence of psychosis or prodromal features. We will also collect blood samples from deletion carriers and related controls and bank these materials in the Rutgers University Cell and DNA Repository (RUCDR) for use by the research community. Finally, we will model the human neuronal phenotype using iPSC lines derived from deletion carriers who have psychosis. This will be the first human neuronal model of the 3q29 deletion. Understanding the specific biological processes disrupted by deletion of the 22 genes in this interval may provide a molecular window into key neurodevelopmental processes relevant to neuropsychiatric phenotypes. All phenotypic data, molecular data, and cell lines will be rapidly shared through NDAR, dbGaP (dbgap.ncbi.nlm.nih.gov) and the NIMH Repository and Genomics Resource (nimhgenetics.org).