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PMID: 22102821 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Relative burden of large CNVs on a range of neurodevelopmental phenotypes.

PLoS genetics ·Vol. 7 ·No. 11 ·2011-11-00 ·Pages e1002334

Girirajan S, Brkanac Z, Coe BP, Baker C, Vives L, Vu TH, Shafer N, Bernier R, Ferrero GB, Silengo M, Warren ST, Moreno CS, Fichera M, Romano C, Raskind WH, Eichler EE

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).

MeSH Terms
Adolescent Autistic Disorder/diagnosis,genetics,pathology Child Comparative Genomic Hybridization/methods Cytoskeletal Proteins DNA Copy Number Variations/genetics Dyslexia/diagnosis,genetics,pathology Endopeptidases/genetics Female Forkhead Transcription Factors/genetics Genetic Association Studies Genetic Predisposition to Disease Humans Intellectual Disability/diagnosis,genetics,pathology Male Nervous System Malformations/genetics,pathology Neurogenesis/genetics,immunology Phenotype Proteins/genetics Repressor Proteins/genetics Sequence Deletion/genetics Transcription Factors
Chemicals
AUTS2 protein, human Cytoskeletal Proteins FOXP1 protein, human Forkhead Transcription Factors Proteins Repressor Proteins Transcription Factors Endopeptidases IMMP2L protein, human
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Girirajan Santhosh
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, United States of America.
Brkanac Zoran
Coe Bradley P
Baker Carl
Vives Laura
Vu Tiffany H
Shafer Neil
Bernier Raphael
Ferrero Giovanni B
Silengo Margherita
Warren Stephen T
Moreno Carlos S
Fichera Marco
Romano Corrado
Raskind Wendy H
Eichler Evan E
Conflict of Interest

EEE is on the scientific advisory board for Pacific Biosciences.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1002334
Published
2011-11-00
Epub
2011-00-10
Pages
e1002334
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC3213131
Subset
IM
Grants
NICHD NIH HHS · R01 HD054562 · United States
Wellcome Trust · United Kingdom
NICHD NIH HHS · 1R01 HD065285 · United States
NICHD NIH HHS · 5R01 HD054562 · United States
Howard Hughes Medical Institute · United States
NICHD NIH HHS · R01 HD065285 · United States
External Links
PubMed source DOI: 10.1371/journal.pgen.1002334 PMC Full Text View journal details
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