Relative burden of large CNVs on a range of neurodevelopmental phenotypes

Santhosh Girirajan, Zoran Brkanac, Bradley P. Coe, Carl Baker, Laura Vives, Tiffany H. Vu, Neil Shafer, Raphael Bernier, Giovanni B. Ferrero, Margherita Silengo, Stephen T. Warren, Carlos S. Moreno, Marco Fichera, Corrado Romano, Wendy H. Raskind, Evan E. Eichler

Research output: Contribution to journalArticlepeer-review

248 Scopus citations


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).

Original languageEnglish (US)
Article numbere1002334
JournalPLoS genetics
Issue number11
StatePublished - Nov 2011

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research


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