Neuroimaging of the schizophrenia-associated 3q29 deletion

摘要 3q29缺失综合征是由复发的1.6Mb杂合性缺失引起的 它与一系列神经精神表型有关，包括轻度到中度 智力残疾、自闭症、焦虑，精神分裂症的风险增加40倍。尽管 3q29缺失是罕见的(约每30,000名新生儿中就有1例)，其高风险为神经精神病学表型 以其相对较低的复杂性(22个基因在缺失区间)提示了病理生理 可能会屈服于审问。对分子、细胞和行为后果的研究 在人类患者和模型系统中，我们的团队和其他人正在进行删除。 然而，大脑结构和功能的障碍还没有阐明，我们建议 使用结构、弥散和静息状态功能磁共振对其进行研究。这是第一次 3q29缺失的神经影像研究。为了达到我们的目标，我们建立了 Emory 3q29项目(http://genome.emory.edu/3q29/)，，主要目标是 了解3q29缺失相关表型的基础。我们还创建了3q29 删除登记处(3q29deletion.org)，尽管删除的人口频率很低 (30,000人中有1人)我们已经确定了100多名携带者(年龄从1.5岁到34岁不等)， 有史以来最大的一群人。这个基础设施，连同我们现有的NIH资助的赠款 (《精神分裂症相关3q29缺失的人类神经元表型建模》，MPI Mulle/Bassell，1 R01 MH110701)，允许我们进行面对面的表型评估 3q29例缺失患者，产生了丰富的行为和临床数据。这项现有的努力， 虽然令人兴奋，但缺乏大脑系统层面的综合数据收集。我们建议增加 这一额外的数据收集维度是我们正在进行的工作的一部分，以便识别体积、 结构连通性和功能连通性变化是3q29的特征 缺失综合征。我们还将对3q29缺失和另一个变体进行比较 与精神分裂症的极高风险，众所周知的22q11.2缺失。定义 3q29缺失对脑系统的影响可能是连接分子的基本环节 缺陷和行为表现。

SUMMARY 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) suggest the pathophysiology may yield to interrogation. Studies of the molecular, cellular, and behavioral consequences of the deletion, in both human patients and model systems, are underway by our group and others. However, disturbances in brain structure and function are not yet articulated, and we propose to investigate them using structural, diffusion, and resting-state functional MRI. This is the first neuroimaging study of the 3q29 deletion. To accomplish our aims, we have established the Emory 3q29 Project (http://genome.emory.edu/3q29/), where the overarching goal is to understand the basis of 3q29 deletion-associated phenotypes. We have also created the 3q29 deletion registry (3q29deletion.org), where despite the low population frequency of the deletion (1 in 30,000) we have ascertained over 100 carriers (ranging in age from 1.5 – 34 years), the largest cohort ever assembled. This infrastructure, along with our existing NIH-funded grant (“Modeling the Human Neuronal Phenotype of the Schizophrenia-Associated 3q29 Deletion,” MPI Mulle/Bassell, 1 R01 MH110701), allows us to conduct in-person phenotypic assessments of 3q29 deletion patients, generating a rich set of behavioral and clinical data. This existing effort, while exciting, lacks integrated collection of data at the level of brain systems. We propose adding this additional dimension of data collection to our ongoing effort in order to identify volumetric, structural connectivity, and functional connectivity alterations that are characteristic of 3q29 deletion syndrome. We will also perform a comparison between 3q29 deletion and another variant with an extremely high risk for schizophrenia, the well-known 22q11.2 deletion. Defining the impact of the 3q29 deletion on brain systems may serve as a fundamental link bridging molecular deficits and behavioral manifestations.