TY - JOUR
T1 - Relative burden of large CNVs on a range of neurodevelopmental phenotypes
AU - Girirajan, Santhosh
AU - Brkanac, Zoran
AU - Coe, Bradley P.
AU - Baker, Carl
AU - Vives, Laura
AU - Vu, Tiffany H.
AU - Shafer, Neil
AU - Bernier, Raphael
AU - Ferrero, Giovanni B.
AU - Silengo, Margherita
AU - Warren, Stephen T.
AU - Moreno, Carlos S.
AU - Fichera, Marco
AU - Romano, Corrado
AU - Raskind, Wendy H.
AU - Eichler, Evan E.
PY - 2011/11
Y1 - 2011/11
N2 - 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).
AB - 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).
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U2 - 10.1371/journal.pgen.1002334
DO - 10.1371/journal.pgen.1002334
M3 - Article
C2 - 22102821
AN - SCOPUS:81755183108
SN - 1553-7390
VL - 7
JO - PLoS genetics
JF - PLoS genetics
IS - 11
M1 - e1002334
ER -