Neuroimaging Findings in Neurodevelopmental Copy Number Variants: Identifying Molecular Pathways to Convergent Phenotypes

Abstract

Genomic copy number variants (CNVs) are associated with a high risk of neurodevelopmental disorders. A growing body of genetic studies suggests that these high-risk genetic variants converge in common molecular pathways and that common pathways also exist across clinically distinct disorders, such as schizophrenia and autism spectrum disorder. A key question is how common molecular mechanisms converge into similar clinical outcomes. We review emerging evidence for convergent cognitive and brain phenotypes across distinct CNVs. Multiple CNVs were shown to have similar effects on core sensory, cognitive, and motor traits. Emerging data from multisite neuroimaging studies have provided valuable information on how these CNVs affect brain structure and function. However, most of these studies examined one CNV at a time, making it difficult to fully understand the proportion of shared brain effects. Recent studies have started to combine neuroimaging data from multiple CNV carriers and identified similar brain effects across CNVs. Some early findings also support convergence in CNV animal models. Systems biology, through integration of multilevel data, provides new insights into convergent molecular mechanisms across genetic risk variants (e.g., altered synaptic activity). However, the link between such key molecular mechanisms and convergent psychiatric phenotypes is still unknown. To better understand this link, we need new approaches that integrate human molecular data with neuroimaging, cognitive, and animal model data, while taking into account critical developmental time points. Identifying risk mechanisms across genetic loci can elucidate the pathophysiology of neurodevelopmental disorders and identify new therapeutic targets for cross-disorder applications.

Keywords: Autism; Copy number variant; Diffusion tensor imaging; Neuroimaging; Schizophrenia; Systems biology.