The schizophrenia-associated 3q29 deletion: genetic architecture of behavioral phenotypes

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Summary 3q29 deletion syndrome is caused by a typically de novo 1.6 Mb deletion of 21 genes. The syndrome is associated with an astonishing 40-fold increased risk for schizophrenia, as well as cognitive disability, a high rate of autism and social disability, executive function deficits and pronounced prevalence of attention deficit hyperactivity disorder (ADHD), clinically significant graphomotor weakness, and manifestation of anxiety disorders. The factors that contribute to this phenotypic heterogeneity are not understood. We propose to evaluate 200 individuals with the 3q29 deletion, to better define phenotypic manifestations and identify risk modifiers for key phenotypes. In particular, we seek to understand how polygenic background and sex of the proband may modify risk for psychosis, cognitive disability, social functioning, and other phenotypes. To facilitate our evaluation and attenuate ascertainment bias, we have developed a remote phenotyping battery, which does not require travel to a testing site. This remote battery removes barriers to participation for our study subjects and dramatically reduces costs, improving the efficiency of our study. Using this validated phenotyping protocol, we will characterize 200 new study subjects with the 3q29 deletion, and identify the full phenotypic spectrum, sex-dependent phenotypic risks and significant comorbid relationships. We will also phenotype biological parents to contextualize the burden of illness in 3q29 deletion syndrome relative to departure from mid-parental phenotype, and clarify the range of phenotypic heterogeneity in 3q29 deletion syndrome. We will collect DNA from our study subjects, to directly test the contribution of polygenic risk to selected phenotypes. Finally, in a collaboration with the NIMH-sponsored Genes 2 Mental Health Network, we will compare the phenotypic spectrum and risk modifiers of 3q29 deletion syndrome with >2,000 samples from other genomic disorders associated with neurodevelopmental and neuropsychiatric disorders, including 22q11.2 deletion and duplication, 16p11 deletion and duplication, 1q21 deletion, and others. At the end of this project, we will have a comprehensive survey of 3q29 deletion associated phenotypes, an understanding of how sex and polygenic background may increase or attenuate phenotypic risks in 3q29 deletion syndrome, and an appreciation for how the 3q29 deletion compares to the broader landscape of rare genetic disorders associated with developmental brain disorders. All genotype and phenotype data from this study will be shared in publicly-available databases, including dbGaP and NDAR.