Neuroimaging of the schizophrenia-associated 3q29 deletion

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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.