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Mol Psychiatry. 2015 Nov;20(11):1366-72. doi: 10.1038/mp.2014.150. Epub 2014 Nov 25.

The phenotypic manifestations of rare genic CNVs in autism spectrum disorder.

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Department of Psychiatry, Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland.
Centre for Support and Training in Analysis and Research, University College Dublin, Dublin 4, Ireland.
Program in Genetics and Genome Biology, Hospital for Sick Children, Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
Departments of Psychiatry, and Genetics and Genomic Sciences, Seaver Autism Center, The Mindich Child Health & Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Molecular Genetics, The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
The Division of Child and Adolescent Psychiatry, Centre for Addiction and Mental Health, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.


Significant evidence exists for the association between copy number variants (CNVs) and Autism Spectrum Disorder (ASD); however, most of this work has focused solely on the diagnosis of ASD. There is limited understanding of the impact of CNVs on the 'sub-phenotypes' of ASD. The objective of this paper is to evaluate associations between CNVs in differentially brain expressed (DBE) genes or genes previously implicated in ASD/intellectual disability (ASD/ID) and specific sub-phenotypes of ASD. The sample consisted of 1590 cases of European ancestry from the Autism Genome Project (AGP) with a diagnosis of an ASD and at least one rare CNV impacting any gene and a core set of phenotypic measures, including symptom severity, language impairments, seizures, gait disturbances, intelligence quotient (IQ) and adaptive function, as well as paternal and maternal age. Classification analyses using a non-parametric recursive partitioning method (random forests) were employed to define sets of phenotypic characteristics that best classify the CNV-defined groups. There was substantial variation in the classification accuracy of the two sets of genes. The best variables for classification were verbal IQ for the ASD/ID genes, paternal age at birth for the DBE genes and adaptive function for de novo CNVs. CNVs in the ASD/ID list were primarily associated with communication and language domains, whereas CNVs in DBE genes were related to broader manifestations of adaptive function. To our knowledge, this is the first study to examine the associations between sub-phenotypes and CNVs genome-wide in ASD. This work highlights the importance of examining the diverse sub-phenotypic manifestations of CNVs in ASD, including the specific features, comorbid conditions and clinical correlates of ASD that comprise underlying characteristics of the disorder.

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