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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH076431-04
Application #
7479329
Study Section
Special Emphasis Panel (ZMH1-ERB-L (06))
Program Officer
Lehner, Thomas
Project Start
2005-09-30
Project End
2010-07-31
Budget Start
2008-09-10
Budget End
2009-07-31
Support Year
4
Fiscal Year
2008
Total Cost
$404,440
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
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Antaki, Danny; Brandler, William M; Sebat, Jonathan (2018) SV2: accurate structural variation genotyping and de novo mutation detection from whole genomes. Bioinformatics 34:1774-1777
Grochowski, Christopher M; Gu, Shen; Yuan, Bo et al. (2018) Marker chromosome genomic structure and temporal origin implicate a chromoanasynthesis event in a family with pleiotropic psychiatric phenotypes. Hum Mutat 39:939-946
Brandler, William M; Antaki, Danny; Gujral, Madhusudan et al. (2016) Frequency and Complexity of De Novo Structural Mutation in Autism. Am J Hum Genet 98:667-79
Brandler, William M; Sebat, Jonathan (2015) From de novo mutations to personalized therapeutic interventions in autism. Annu Rev Med 66:487-507
Kusenda, Mary; Vacic, Vladimir; Malhotra, Dheeraj et al. (2015) The Influence of Microdeletions and Microduplications of 16p11.2 on Global Transcription Profiles. J Child Neurol 30:1947-53
Corominas, Roser; Yang, Xinping; Lin, Guan Ning et al. (2014) Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism. Nat Commun 5:3650
Malhotra, Dheeraj; Sebat, Jonathan (2012) CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148:1223-41
Michaelson, Jacob J; Shi, Yujian; Gujral, Madhusudan et al. (2012) Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 151:1431-42
Michaelson, Jacob J; Sebat, Jonathan (2012) forestSV: structural variant discovery through statistical learning. Nat Methods 9:819-21

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