Copy Number Variation in Neurodevelopmental Disorders

Rare copy number variants (CNVs) have key roles in the genetic etiologies of different neurodevelopmental conditions such as Autism Spectrum Disorder (ASD), schizophrenia and ADHD. The study of such rare deletions and duplications in the genomes of patients has proven to be a powerful strategy for the rapid identification of novel risk genes. This work features the high resolution microarray CNV analysis of three Canadian cohorts of 1,418 individuals with different neurodevelopmental disorders (ASD, ADHD and schizophrenia). These analyses confirmed regions previously implicated in genetic risk for neurodevelopmental disorders, and also revealed novel CNV loci such as deletions affecting NRXN3 in ASD. Cross-disorder rare CNV comparisons highlighted several shared risk genes including ASTN2/TRIM32 in ASD and ADHD and GPHN in ASD and schizophrenia. Follow-up clinical and molecular characterization of these CNVs revealed factors modulating their penetrance including gender and isoform-specific effects. These results provide support for the role of rare CNVs in the genetic etiologies of ASD, ADHD and schizophrenia; provide evidence for shared susceptibility genes for different neuropsychiatric disorders; and identify new risk genes to guide clinical genetic testing as well as the development of molecular therapeutics.