Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes

Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes

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 customiz...

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Main Authors: Girirajan, Santhosh, 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.
Format: Online
Language:English
Published: Public Library of Science 2011
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213131/
id pubmed-3213131
recordtype oai_dc
spelling pubmed-32131312011-11-18 Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes Girirajan, Santhosh 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. Research Article 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). Public Library of Science 2011-11-10 /pmc/articles/PMC3213131/ /pubmed/22102821 http://dx.doi.org/10.1371/journal.pgen.1002334 Text en Girirajan et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Girirajan, Santhosh
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.
spellingShingle Girirajan, Santhosh
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.
Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes
author_facet Girirajan, Santhosh
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.
author_sort Girirajan, Santhosh
title Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes
title_short Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes
title_full Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes
title_fullStr Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes
title_full_unstemmed Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes
title_sort relative burden of large cnvs on a range of neurodevelopmental phenotypes
description 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).
publisher Public Library of Science
publishDate 2011
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213131/
_version_ 1611486782504828928

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