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Autism spectrum disorders (ASDs) are highly heritable, yet relatively few associated genetic loci have been replicated. Copy number variations (CNVs) have been implicated in autism; however, the majority of loci contribute to &lt;1% of the disease population. Therefore, independent studies are important to refine associated CNV regions and discover novel susceptibility genes. In this study, a genome-wide SNP array was utilized for CNV detection by two distinct algorithms in a European ancestry case–control data set. We identify a significantly higher burden in the number and size of deletions, and disrupting more genes in ASD cases. Moreover, 18 deletions larger than 1 Mb were detected exclusively in cases, implicating novel regions at 2q22.1, 3p26.3, 4q12 and 14q23. Case-specific CNVs provided further evidence for pathways previously implicated in ASDs, revealing new candidate genes within the GABAergic signaling and neural development pathways. These include  DBI , an allosteric binder of GABA receptors,  GABARAPL1 , the GABA receptor-associated protein, and  SLC6A11 , a postsynaptic GABA transporter. We also identified CNVs in  COBL , deletions of which cause defects in neuronal cytoskeleton morphogenesis in model vertebrates, and  DNER , a neuron-specific Notch ligand required for cerebellar development. Moreover, we found evidence of genetic overlap between ASDs and other neurodevelopmental and neuropsychiatric diseases. These genes include glutamate receptors ( GRID1 ,  GRIK2  and  GRIK4 ), synaptic regulators ( NRXN3 ,  SLC6A8  and  SYN3 ), transcription factor (ZNF804A) and RNA-binding protein  FMR1 . Taken together, these CNVs may be a few of the missing pieces of ASD heritability and lead to discovering novel etiological mechanisms.

Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways