Copy Number Variation in Neurodevelopmental Disorders

Recent research on genetic etiologies of different neurodevelopmental conditions such as Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD) and schizophrenia has highlighted a key role for rare copy number variants (CNVs). The study of such rare deletions and duplications in the genomes of patients has proven to be a powerful strategy for rapid identification of novel risk genes. Intriguingly, there is an emerging pattern of certain genes being implicated by rare CNVs across clinically distinct disorders. Findings of genetic overlap are consistent with comorbidity and shared traits often observed among these conditions and hint at common underlying biological processes or pathways such as synaptic development. This trend of overlapping genetic loci predisposing to different phenotypes has not been systematically investigated in an unbiased fashion on a genome-wide scale.;In this thesis, I describe high resolution microarray analysis of three newly characterized Canadian cohorts of individuals with different neurodevelopmental disorders (ASD, ADHD and schizophrenia) in a uniform manner and with two main objectives. First, within each cohort, rare CNVs were detected and used to identify new genetic risk loci for each disorder. My prioritization strategy focused on rare CNVs of two types: those of de novo origin and those significantly enriched in multiple unrelated patients compared to controls. Second, overlapping rare CNVs among the three cohorts were further investigated to assess cross-disorder genetic overlap and pinpoint shared risk genes.;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, MACROD2/FLRT3 in ADHD and the 2q13 region in schizophrenia. 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.