CIENCIASMEDICASNEWS: AJHG - Genome-wide Transcriptome Profiling Reveals the Functional Impact of Rare De Novo and Recurrent CNVs in Autism Spectrum Disorders

domingo, 1 de julio de 2012

AJHG - Genome-wide Transcriptome Profiling Reveals the Functional Impact of Rare De Novo and Recurrent CNVs in Autism Spectrum Disorders

Copyright © 2012 The American Society of Human Genetics All rights reserved.
The American Journal of Human Genetics, 21 June 2012

doi:10.1016/j.ajhg.2012.05.011

Article

Genome-wide Transcriptome Profiling Reveals the Functional Impact of Rare De Novo and Recurrent CNVs in Autism Spectrum Disorders

Rui Luo¹^,², Stephan J. Sanders³^,⁴^,⁵^,⁶, Yuan Tian²^,⁷, Irina Voineagu²^,⁸, Ni Huang⁹^,¹³, Su H. Chu¹⁰^,¹³, Lambertus Klei¹²^,¹³, Chaochao Cai¹^,¹¹, Jing Ou²^,⁸, Jennifer K. Lowe²^,⁸, Matthew E. Hurles⁹^,¹³, Bernie Devlin¹²^,¹³, Matthew W. State³^,⁴^,⁵^,⁶ and Daniel H. Geschwind¹^,²^,⁸^,^,

¹ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
² Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
³ Program on Neurogenetics, Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA
⁴ Program on Human Genetics and Genomics, Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA
⁵ Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA
⁶ Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA
⁷ Interdepartmental PhD Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA
⁸ Neurogenetics Program, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
⁹ Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
¹⁰ Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA
¹¹ Department of Biostatistics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
¹² Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

Corresponding author

¹³ These authors contributed equally to this work

Abstract

Copy-number variants (CNVs) are a major contributor to the pathophysiology of autism spectrum disorders (ASDs), but the functional impact of CNVs remains largely unexplored. Because brain tissue is not available from most samples, we interrogated gene expression in lymphoblasts from 244 families with discordant siblings in the Simons Simplex Collection in order to identify potentially pathogenic variation. Our results reveal that the overall frequency of significantly misexpressed genes (which we refer to here as outliers) identified in probands and unaffected siblings does not differ. However, in probands, but not their unaffected siblings, the group of outlier genes is significantly enriched in neural-related pathways, including neuropeptide signaling, synaptogenesis, and cell adhesion. We demonstrate that outlier genes cluster within the most pathogenic CNVs (rare de novo CNVs) and can be used for the prioritization of rare CNVs of potentially unknown significance. Several nonrecurrent CNVs with significant gene-expression alterations are identified (these include deletions in chromosomal regions 3q27, 3p13, and 3p26 and duplications at 2p15), suggesting that these are potential candidate ASD loci. In addition, we identify distinct expression changes in 16p11.2 microdeletions, 16p11.2 microduplications, and 7q11.23 duplications, and we show that specific genes within the 16p CNV interval correlate with differences in head circumference, an ASD-relevant phenotype. This study provides evidence that pathogenic structural variants have a functional impact via transcriptome alterations in ASDs at a genome-wide level and demonstrates the utility of integrating gene expression with mutation data for the prioritization of genes disrupted by potentially pathogenic mutations.