A Discovery Resource of Rare Copy Number Variations in Individuals with Autism Spectrum Disorder

G3: Genes, Genomes, Genetics

Daniele Merico⁵  Peggy S. Eis⁴  John Wei⁵  Peter Szatmari⁷  Wendy Roberts²  Jessica Rickaby⁵  Bridget A. Fernandez⁶  Stephen W. Scherer⁸  Anath C. Lionel¹  Eli Hatchwell⁴  Chao Lu⁵  Aparna Prasad⁵  Bhooma Thiruvahindrapuram⁵  Christian R. Marshall³  Daisuke Sato⁵ 

[1] The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, CDepartment of Molecular Genetics, University of Toronto, Toronto M5G 1L7, CThe Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, CThe Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, CDepartment of Molecular Genetics, University of Toronto, Toronto M5G 1L7, CDepartment of Molecular Genetics, University of Toronto, Toronto M5G 1L7, CThe Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, CDepartment of Molecular Genetics, University of Toronto, Toronto M5G 1L7, C;Autism Research Unit, The Hospital for Sick Children, Toronto M5G 1X8, CAutism Research Unit, The Hospital for Sick Children, Toronto M5G 1X8, CAutism Research Unit, The Hospital for Sick Children, Toronto M5G 1X8, C;The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, CMcLaughlin Centre, University of Toronto, Toronto M5G 1L7, CThe Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, CThe Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, CMcLaughlin Centre, University of Toronto, Toronto M5G 1L7, CMcLaughlin Centre, University of Toronto, Toronto M5G 1L7, CThe Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, CMcLaughlin Centre, University of Toronto, Toronto M5G 1L7, C;Population Diagnostics, Inc., Melville, New York 11747Population Diagnostics, Inc., Melville, New York 11747Population Diagnostics, Inc., Melville, New York 11747;The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, CThe Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, CThe Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, C;Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland A1B 3V6, CDisciplines of Genetics and Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland A1B 3V6, CDisciplines of Genetics and Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland A1B 3V6, C;Offord Centre for Child Studies, Department of Psychiatry and Behavioural Neurosciences McMaster University, Hamilton L8P 3B6, COfford Centre for Child Studies, Department of Psychiatry and Behavioural Neurosciences McMaster University, Hamilton L8P 3B6, COfford Centre for Child Studies, Department of Psychiatry and Behavioural Neurosciences McMaster University, Hamilton L8P 3B6, C;The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, CDepartment of Molecular Genetics, University of Toronto, Toronto M5G 1L7, CMcLaughlin Centre, University of Toronto, Toronto M5G 1L7, CThe Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, CThe Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, CDepartment of Molecular Genetics, University of Toronto, Toronto M5G 1L7, CMcLaughlin Centre, University of Toronto, Toronto M5G 1L7, CDepartment of Molecular Genetics, University of Toronto, Toronto M5G 1L7, CThe Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, CDepartment of Molecular Genetics, University of Toronto, Toronto M5G 1L7, CMcLaughlin Centre, University of Toronto, Toronto M5G 1L7, CMcLaughlin Centre, University of Toronto, Toronto M5G 1L7, CThe Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 1L7, CDepartment of Molecular Genetics, University of Toronto, Toronto M5G 1L7, CMcLaughlin Centre, University of Toronto, Toronto M5G 1L7, C

关键词: rare variants;    gene copy number;    chromosomal abnormalities;    cytogenetics;    molecular pathways;   

DOI  :  10.1534/g3.112.004689

学科分类：生物科学（综合）

来源: Genetics Society of America

【 摘 要 】

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.

【 授权许可】

Unknown