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

项目总结/摘要 3q 29缺失综合征是由复发性典型的从头1.6 Mb杂合缺失引起的， 与一系列神经精神表型相关，包括轻度至中度智力残疾， 孤独症，焦虑症，精神分裂症的风险增加40倍。尽管3q 29缺失很罕见（约为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个基因中， 缺失间隔）使其成为分子解剖的理想选择。研究3q 29引起的神经元表型 缺失可能揭示了精神分裂症、自闭症和/或自闭症中被破坏的核心神经发育过程 智力残疾。我们建议评估缺失携带者的行为特征沿着4个维度：认知 能力、焦虑、自闭症谱系和精神病或前驱症状的存在。我们也会收集血液 从缺失载体和相关对照中提取样品，并将这些材料储存在罗格斯大学细胞中， DNA储存库（RUCDR）供研究界使用。最后，我们将模拟人类神经元 表型使用源自具有精神病的缺失携带者的iPSC系。这将是第一个人类 3q 29缺失的神经元模型。了解被删除破坏的特定生物过程 该区间的22个基因中的一个可能为了解关键神经发育过程提供了分子窗口 与神经精神表型有关。所有的表型数据、分子数据和细胞系都将被快速地 通过NDAR、dbGaP（dbgap.ncbi.nlm.nih.gov）和NIMH知识库和基因组学资源共享 （nimhgenetics.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).