Integrative Molecular and Phenotype Analysis of 22q11.2 Deletion Syndrome

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DESCRIPTION (provided by applicant): 22q11.2 microdeletion syndrome (Velocardiofacial Syndrome; 22q11DS) occurs in about 1/3000 live births, and is the most frequent known recurrent genetic cause of schizophrenia, accounting for 1-2 % of schizophrenia cases in the general population The overall goal of this project is to study neural progrenitors and neurons derived from human induced pluripotent stem cells (iPSCs), in order to identify the cellular and molecular mechanisms underlying the neuropsychiatric phenotype in patients with 22q11DS. In the last five years we have developed highly reproducible methods for studying the differentiation of iPSCs into neurons, and for characterizing these cells using well-validated genetic and cell biological assays. Using this approach, we found evidence of reproducible changes in gene expression that implicate calcium (CA) signaling and developmental dysregulation in 22q11DS neurons. We experimentally validated the presence of aberrant CA signaling and dopaminergic D2 receptor dysfunction, as well as defects in dendritic branching. We now have the technology in place to significantly increase the throughput, and in this study we will expand our investigations to a much larger sample of patients with 22q11DS, in order to connect the cellular defects with patient characteristics. Specifically, we will: 1) generate an iPSC patient resource by obtaining skin fibroblasts from 40 well-characterized patients with 22q11DS - 20 with a diagnosis of psychotic disorder and 20 without - and 20 demographically comparable controls. 2) Using these resources, we will first validate our preliminary findings of defects in dopaminergic signaling, and then determine which aspects of calcium signaling are impacted by the deletion. By rescuing the phenotype through selectively expressing each of the genes deleted within the 22q11.2 region we will determine which gene(s) are causally implicated in the specific defects. 3) In parallel, we will comprehensively analyze the transcriptome in order to identify key hubs and pathways that are dysregulated in neurons from 22q11DS patients, and compare the co-expression modules in 22q11DS patients with and without psychosis, to explore potential pathways that may be specifically relevant to the development of schizophrenia in 22q11DS. Finally we will: 4) connect cellular, gene expression and behavioral phenotypes, by comparing cellular phenotypes derived from 22q11DS patients with and without psychosis, which will be integrated with gene expression data, in order to connect molecular pathways to morphological or physiological phenotypes, and actual clinical presentations in 22q11DS patients.