Autism is a neuropsychiatric disorder characterized by deficits in social interaction and communication, and unusual and repetitive behavior. The causes of autism are poorly understood. It has been clearly determined that genes play a major role in the etiology of the disease, and autism has been linked to a few rare single gene mutations, as well as many visible chromosomal abnormalties resulting in changes in gene copy number;however, the majority causes of autism remain undetermined. We hypothesize that alterations in gene dosage including heritable copy number polymorphisms (CNPs) are an underlying basis for autism. We have developed a powerful approach for identifying CNPs: Representational Oligonucleotide Microarray Analysis (ROMA). By whole-genome ROMA scans of patients from the Autism Genetic Resource Exchange (AGRE), we previously identified familial copy number variants that are significantly more frequent in autism than in controls. We propose to determine the role of CNPs in autism by determining disease association of CNPs in concordant sibling pairs. Using a """"""""candidate chip"""""""" approach, we will screen the entire AGRE sample by ROMA (500 families) using an array that targets 200 candidate CNPs at a resolution 6 kb. We will determine the association of CNPs by the proportion of allele-sharing in siblings;in addition, we will examine CNPs for parent-of-origin effects. The relevance of specific CNPs to autism will be further evaluated by examining the genomic position of autism CNPs with respect to candidate regions from previous linkage and cytogenetic studies. We will determine the exact gene content of CNPs and examine the potential role of individual genes in cognitive function and disease. Lastly, we will investigate a link between individual structural variants and subtypes of autism with distinguishable clinical profiles such as specific cognitive and motor defects, brain abnormalities, craniofacial dysmorphism and comorbidity with other disorders. The results of this study will make substantial contributions to our knowledge of the causes of autism and the role of specific genes in cognitive development. Recognition of specific disorders of the autism spectrum caused by small copy number polymorphisms will improve treatment and prognosis, as well as genetic counseling for families with autism.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1-ERB-L (06))
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Lehner, Thomas
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Cold Spring Harbor Laboratory
Cold Spring Harbor
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Brandler, William M; Antaki, Danny; Gujral, Madhusudan et al. (2018) Paternally inherited cis-regulatory structural variants are associated with autism. Science 360:327-331
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