High frequency of rare copy number variants affecting functionally related genes in patients with structural brain malformations

Authors

  • Roxana Kariminejad,

    1. Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran
    2. Max Planck Institute for Molecular Genetics, Berlin, Germany
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    • These authors contributed equally to this work.

  • Allan Lind-Thomsen,

    1. Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark
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    • These authors contributed equally to this work.

  • Zeynep Tümer,

    1. Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark
    Current affiliation:
    1. Applied Human Molecular Genetics, Kennedy Center, Glostrup, Denmark
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  • Fikret Erdogan,

    1. Max Planck Institute for Molecular Genetics, Berlin, Germany
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  • Hans H. Ropers,

    1. Max Planck Institute for Molecular Genetics, Berlin, Germany
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  • Niels Tommerup,

    Corresponding author
    1. Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark
    • Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark
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  • Reinhard Ullmann,

    Corresponding author
    1. Max Planck Institute for Molecular Genetics, Berlin, Germany
    • Max Planck Institute for Molecular Genetics, Ihnestr. 73, 14195 Berlin, Germany
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  • Rikke S. Møller

    1. Max Planck Institute for Molecular Genetics, Berlin, Germany
    2. Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark
    3. Danish Epilepsy Centre, Dianalund, Denmark
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  • Communicated by Christine Van Broeckhoven

Abstract

During the past years, significant advances have been made in our understanding of the development of the human brain, and much of this knowledge comes from genetic studies of disorders associated with abnormal brain development. We employed array-comparative genomic hybridization (CGH) to investigate copy number variants (CNVs) in a cohort of 169 patients with various structural brain malformations including lissencephaly, polymicrogyria, focal cortical dysplasia, and corpus callosum agenesis. The majority of the patients had intellectual disabilities (ID) and suffered from symptomatic epilepsy. We detected at least one rare CNV in 38 patients (22.5%). All genes located within the rare CNVs were subjected to enrichment analysis for specific Gene Ontology Terms or Kyoto Encyclopedia of Genes and Genomes pathways and to protein–protein network analysis. Based on these analyses, we propose that genes involved in “axonal transport,” “cation transmembrane transporter activity,” and the “c-Jun N-terminal kinase (JNK) cascade” play a significant role in the etiology of brain malformations. This is to the best of our knowledge the first systematic study of CNVs in patients with structural brain malformations and our data show that CNVs play an important role in the etiology of these malformations, either as direct causes or as genetic risk factors. 32:1427–1435, 2011. ©2011 Wiley Periodicals, Inc.

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