title: A discovery resource of rare copy number variations in individuals with autism spectrum disorder.
abstract: 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.
authors.affiliation: The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, Canada.
authors.forename: Aparna
authors.initials: A
authors.lastname: Prasad
authors.forename: Daniele
authors.initials: D
authors.lastname: Merico
authors.forename: Bhooma
authors.initials: B
authors.lastname: Thiruvahindrapuram
authors.forename: John
authors.initials: J
authors.lastname: Wei
authors.forename: Anath C
authors.initials: AC
authors.lastname: Lionel
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sato
authors.forename: Jessica
authors.initials: J
authors.lastname: Rickaby
authors.forename: Chao
authors.initials: C
authors.lastname: Lu
authors.forename: Peter
authors.initials: P
authors.lastname: Szatmari
authors.forename: Wendy
authors.initials: W
authors.lastname: Roberts
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Fernandez
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.forename: Eli
authors.initials: E
authors.lastname: Hatchwell
authors.forename: Peggy S
authors.initials: PS
authors.lastname: Eis
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
mesh_terms: D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
keywords: chromosomal abnormalities; cytogenetics; gene copy number; molecular pathways; rare variants