title: Relative burden of large CNVs on a range of neurodevelopmental phenotypes.
abstract: While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (>1 Mbp) is significantly greater for ID-associated phenotypes compared to autism (p = 9.58 × 10(-11), odds ratio = 4.59), dyslexia (p = 3.81 × 10(-18), odds ratio = 14.45), or controls (p = 2.75 × 10(-17), odds ratio = 13.71). There is a striking difference in the frequency of rare CNVs (>50 kbp) in autism (10%, p = 2.4 × 10(-6), odds ratio = 6) or ID (16%, p = 3.55 × 10(-12), odds ratio = 10) compared to dyslexia (2%) with essentially no difference in large CNV burden among dyslexia patients compared to controls. Rare CNVs were more likely to arise de novo (64%) in ID when compared to autism (40%) or dyslexia (0%). We observed a significantly increased large CNV burden in individuals with ID and multiple congenital anomalies (MCA) compared to ID alone (p = 0.001, odds ratio = 2.54). Our data suggest that large CNV burden positively correlates with the severity of childhood disability: ID with MCA being most severely affected and dyslexics being indistinguishable from controls. When autism without ID was considered separately, the increase in CNV burden was modest compared to controls (p = 0.07, odds ratio = 2.33).
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Girirajan
authors.forename: Zoran
authors.initials: Z
authors.lastname: Brkanac
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Coe
authors.forename: Carl
authors.initials: C
authors.lastname: Baker
authors.forename: Laura
authors.initials: L
authors.lastname: Vives
authors.forename: Tiffany H
authors.initials: TH
authors.lastname: Vu
authors.forename: Neil
authors.initials: N
authors.lastname: Shafer
authors.forename: Raphael
authors.initials: R
authors.lastname: Bernier
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Ferrero
authors.forename: Margherita
authors.initials: M
authors.lastname: Silengo
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Warren
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Moreno
authors.forename: Marco
authors.initials: M
authors.lastname: Fichera
authors.forename: Corrado
authors.initials: C
authors.lastname: Romano
authors.forename: Wendy H
authors.initials: WH
authors.lastname: Raskind
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D000293:Adolescent; D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D002648:Child; D055028:Comparative Genomic Hybridization / Q000379:methods; D003598:Cytoskeletal Proteins; D056915:DNA Copy Number Variations / Q000235:genetics*; D004410:Dyslexia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D010450:Endopeptidases / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D009421:Nervous System Malformations / Q000235:genetics / Q000473:pathology; D055495:Neurogenesis / Q000235:genetics / Q000276:immunology*; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D014157:Transcription Factors
chemical_list: C554283:AUTS2 protein, human; D003598:Cytoskeletal Proteins; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D011506:Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D010450:Endopeptidases; C425070:IMMP2L protein, human
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