title: Indexing Effects of Copy Number Variation on Genes Involved in Developmental Delay.
abstract: A challenge in clinical genomics is to predict whether copy number variation (CNV) affecting a gene or multiple genes will manifest as disease. Increasing recognition of gene dosage effects in neurodevelopmental disorders prompted us to develop a computational approach based on critical-exon (highly expressed in brain, highly conserved) examination for potential etiologic effects. Using a large CNV dataset, our updated analyses revealed significant (P < 1.64 × 10(-15)) enrichment of critical-exons within rare CNVs in cases compared to controls. Separately, we used a weighted gene co-expression network analysis (WGCNA) to construct an unbiased protein module from prenatal and adult tissues and found it significantly enriched for critical exons in prenatal (P < 1.15 × 10(-50), OR = 2.11) and adult (P < 6.03 × 10(-18), OR = 1.55) tissues. WGCNA yielded 1,206 proteins for which we prioritized the corresponding genes as likely to have a role in neurodevelopmental disorders. We compared the gene lists obtained from critical-exon and WGCNA analysis and found 438 candidate genes associated with CNVs annotated as pathogenic, or as variants of uncertain significance (VOUS), from among 10,619 developmental delay cases. We identified genes containing CNVs previously considered to be VOUS to be new candidate genes for neurodevelopmental disorders (GIT1, MVB12B and PPP1R9A) demonstrating the utility of this strategy to index the clinical effects of CNVs.
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Uddin
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pellecchia
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Bhooma
authors.initials: B
authors.lastname: Thiruvahindrapuram
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lia
authors.initials: L
authors.lastname: D'Abate
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Daniele
authors.initials: D
authors.lastname: Merico
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ada
authors.initials: A
authors.lastname: Chan
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Zarrei
authors.affiliation: Center of Neurodevelopmental Disorders (KIND), Neuropsychiatric Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Tammimies
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Walker
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Gazzellone
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nalpathamkalam
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Ryan K C
authors.initials: RK
authors.lastname: Yuen
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Koenraad
authors.initials: K
authors.lastname: Devriendt
authors.affiliation: CHU Sainte-Justine, University de Montreal, Montreal, Quebec, Canada.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Mathonnet
authors.affiliation: CHU Sainte-Justine, University de Montreal, Montreal, Quebec, Canada.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Lemyre
authors.affiliation: CHU Sainte-Justine, University de Montreal, Montreal, Quebec, Canada.
authors.forename: Sonia
authors.initials: S
authors.lastname: Nizard
authors.affiliation: Genome Diagnostics, Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Mary
authors.initials: M
authors.lastname: Shago
authors.affiliation: Genome Diagnostics, Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Joseph-George
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Diagnostic Medical Genetics, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Abdul
authors.initials: A
authors.lastname: Noor
authors.affiliation: Department of Genetics, The Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
authors.forename: Melissa T
authors.initials: MT
authors.lastname: Carter
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 2L3, Canada.
authors.forename: Grace
authors.initials: G
authors.lastname: Yoon
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 2L3, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Kannu
authors.affiliation: CHU Sainte-Justine, University de Montreal, Montreal, Quebec, Canada.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tihy
authors.affiliation: Cytogenetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Thorland
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Genome Diagnostics, Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Buchanan
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marsha
authors.initials: M
authors.lastname: Speevak
authors.affiliation: Genome Diagnostics, Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Dimitri J
authors.initials: DJ
authors.lastname: Stavropoulos
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D040901:Proteomics / Q000379:methods
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C485647:GIT1 protein, human