Journal
G3-GENES GENOMES GENETICS
Volume 2, Issue 12, Pages 1665-1685Publisher
GENETICS SOCIETY AMERICA
DOI: 10.1534/g3.112.004689
Keywords
rare variants; gene copy number; chromosomal abnormalities; cytogenetics; molecular pathways
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Funding
- NeuroDevNet
- University of Toronto McLaughlin Centre
- Genome Canada
- Ontario Genomics Institute
- Canadian Institutes for Health Research (CIHR)
- Canadian Institute for Advanced Research
- Canada Foundation for Innovation
- government of Ontario
- The Hospital for Sick Children Foundation
- CIHR Autism Training Program
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The identification of rare inherited and de novo copy number variations (CNVs) in human subjects has proven a productive approach to highlight risk genes for autism spectrum disorder (ASD). A variety of microarrays are available to detect CNVs, including single-nucleotide polymorphism (SNP) arrays and comparative genomic hybridization (CGH) arrays. Here, we examine a cohort of 696 unrelated ASD cases using a high-resolution one-million feature CGH microarray, the majority of which were previously genotyped with SNP arrays. Our objective was to discover new CNVs in ASD cases that were not detected by SNP microarray analysis and to delineate novel ASD risk loci via combined analysis of CGH and SNP array data sets on the ASD cohort and CGH data on an additional 1000 control samples. Of the 615 ASD cases analyzed on both SNP and CGH arrays, we found that 13,572 of 21,346 (64%) of the CNVs were exclusively detected by the CGH array. Several of the CGH-specific CNVs are rare in population frequency and impact previously reported ASD genes (e. g., NRXN1, GRM8, DPYD), as well as novel ASD candidate genes (e. g., CIB2, DAPP1, SAE1), and all were inherited except for a de novo CNV in the GPHN gene. A functional enrichment test of gene-sets in ASD cases over controls revealed nucleotide metabolism as a potential novel pathway involved in ASD, which includes several candidate genes for follow-up (e. g., DPYD, UPB1, UPP1, TYMP). Finally, this extensively phenotyped and genotyped ASD clinical cohort serves as an invaluable resource for the next step of genome sequencing for complete genetic variation detection.
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