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).
3q29 deletion syndrome is caused by a deletion of DNA, sized 1.6 million bases, and is associated with high risk for intellectual disability, autism, anxiety, and schizophrenia. We propose to characterize the behavioral, cellular, and molecular phenotypes associated with 3q29 deletion syndrome by creating the first human neuronal model of the 3q29 deletion. This project will help us to understand the core pathophysiology underlying neurodevelopment and neuropsychiatric phenotypes.