Sequence analysis of 17 NRXN1 deletions

Authors

  • Louise Kristine Enggaard Hoeffding,

    Corresponding author
    1. Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark
    • Correspondence to:

      Louise Kristine Enggaard Hoeffding, Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Boserupvej 2, DK-4000 Roskilde, Denmark.

      Email: louise.k.enggaard.hoeffding@regionh.dk

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  • Thomas Hansen,

    1. Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark
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  • Andrés Ingason,

    1. Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark
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  • Linh Doung,

    1. Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark
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  • Johan H. Thygesen,

    1. Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark
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  • Rikke S. Møller,

    1. Danish Epilepsy Centre, Dianalund, Denmark
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  • Niels Tommerup,

    1. Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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  • George Kirov,

    1. MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK
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  • Dan Rujescu,

    1. Division of Molecular and Clinical Neurobiology, Department of Psychiatry, University of Munich, Munich, Germany
    2. Department of Psychiatry, University of Halle, Halle, Germany
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  • Lars A. Larsen,

    1. Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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  • Thomas Werge

    1. Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark
    2. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
    3. iPSYCH - The Lundbeck Foundation's Initiative for Integrative Psychiatric Research
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Errata

This article is corrected by:

  1. Errata: Erratum: Sequence analysis of 17 NRXN1 deletions Volume 165, Issue 3, 261, Article first published online: 12 March 2014

  • Study approval: Ethical approval was obtained from the local Ethics Committees. All participants gave written informed consent.
  • Competing interests: All authors included on the paper have declared no conflict of interest. Dr. Werge has served as a lecturer for and consultant to H. Lundbeck A/S.

Abstract

Background

Genome instability plays fundamental roles in human evolution and phenotypic variation within our population. This instability leads to genomic rearrangements that are involved in a wide variety of human disorders, including congenital and neurodevelopmental disorders, and cancers. Insight into the molecular mechanisms governing such genomic rearrangements may increase our understanding of disease pathology and evolutionary processes. Here we analyse 17 carriers of non-recurrent deletions in the NRXN1 gene, which have been associated with neurodevelopmental disorders, e.g. schizophrenia, autism and epilepsies.

Methods

17 non-recurrent NRXN1 deletions identified by GWA were sequenced to map the breakpoints of each. Meme … etc. was used to identify shared patterns between the deletions and compare these were previously studies on non-recurrent deletions.

Results

We discovered two novel sequence motifs shared between all 17 NRXN1 deletions and a significantly higher AT nucleotide content at the breakpoints, compared to the overall nucleotide content on chromosome 2. We found different alteration of sequence at the breakpoint; small insertions and duplications giving rise to short microhomology sequences.

Conclusions

No single mechanism seems to be implicated in the deletion events, but the results suggest that NHEJ, FoSTeS or MMBIR is implicated. The two novel sequence motifs together with a high AT content in all in NRXN1 deletions may lead to increased instability leading to a increase susceptibility to a single stranded structures. This favours potentially repaired by NHEJ mechanism of double strand breaks or may leading to replication errors. © 2013 Wiley Periodicals, Inc.

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