Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism

Neuron. 2011 Jun 9;70(5):863-85. doi: 10.1016/j.neuron.2011.05.002.

Abstract

We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 × 10(-7)). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Cadherins / genetics
  • Cell Adhesion Molecules, Neuronal / genetics
  • Child
  • Child Development Disorders, Pervasive / genetics*
  • Child, Preschool
  • Chromosomes, Human, Pair 16 / genetics*
  • Chromosomes, Human, Pair 7 / genetics*
  • Chromosomes, Human, X / genetics
  • DNA Copy Number Variations / genetics*
  • Family Health*
  • Female
  • Gene Duplication / genetics
  • Gene Expression Profiling
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Nerve Tissue Proteins / genetics
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Proteins / genetics
  • Siblings
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin-Specific Peptidase 7
  • Williams Syndrome / genetics*

Substances

  • Cadherins
  • Cell Adhesion Molecules, Neuronal
  • FOR20 protein, human
  • H-cadherin
  • NRXN1 protein, human
  • Nerve Tissue Proteins
  • Proteins
  • USP7 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Peptidase 7