Neuroimaging of the schizophrenia-associated 3q29 deletion

摘要 3q29 缺失综合征是由典型的复发性 1.6 Mb 杂合性缺失引起的 并与一系列神经精神表型相关，包括轻度至中度 智力障碍、自闭症、焦虑症以及精神分裂症的风险增加 40 倍。虽然 3q29 缺失非常罕见（约每 30,000 名新生儿中就有 1 人缺失），其神经精神表型的风险很高 以其相对较低的复杂性（缺失区间有 22 个基因）表明病理生理学 可能会屈服于审问。分子、细胞和行为后果的研究 我们的团队和其他人正在人类患者和模型系统中进行删除。 然而，大脑结构和功能的紊乱尚未阐明，我们建议 使用结构、扩散和静息态功能 MRI 来研究它们。这是第一个 3q29 缺失的神经影像学研究。为了实现我们的目标，我们制定了 埃默里大学 3q29 项目 (http://genome.emory.edu/3q29/)，其总体目标是 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），尽管删除的人群频率较低 （三万分之一）我们已确定超过 100 名携带者（年龄范围为 1.5 至 34 岁）， 有史以来规模最大的一次集结。该基础设施以及我们现有的 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)，使我们能够进行面对面的表型评估 3q29 缺失患者，生成丰富的行为和临床数据。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。我们建议添加 我们不断努力收集数据的这一额外维度，以确定体积、 3q29 特征的结构连接和功能连接改变 缺失综合症。我们还将对 3q29 缺失和另一个变体进行比较 众所周知的 22q11.2 缺失具有极高的精神分裂症风险。定义 3q29 缺失对大脑系统的影响可能作为桥接分子的基本联系 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.