Contactin 4 as an autism susceptibility locus

Authors

  • Catherine E. Cottrell,

    1. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio
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  • Natalie Bir,

    1. Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
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  • Elizabeth Varga,

    1. Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
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  • Carlos E. Alvarez,

    1. Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    2. Department of Pediatrics, The Ohio State University, Columbus, Ohio
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  • Samuel Bouyain,

    1. Division of Molecular Biology and Biochemistry, School of Biological Sciences, University of Missouri-Kansas City, Kansas City, Missouri
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  • Randall Zernzach,

    1. Department of Pediatrics, Wright-Patterson Air Force Base, Ohio
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  • Devon L. Thrush,

    1. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio
    2. Department of Pediatrics, The Ohio State University, Columbus, Ohio
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  • Johnna Evans,

    1. Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
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  • Michael Trimarchi,

    1. Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
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  • Eric M. Butter,

    1. Department of Pediatrics, The Ohio State University, Columbus, Ohio
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  • David Cunningham,

    1. Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    2. Department of Pediatrics, The Ohio State University, Columbus, Ohio
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  • Julie M. Gastier-Foster,

    1. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio
    2. Department of Pediatrics, The Ohio State University, Columbus, Ohio
    3. Department of Pathology, The Ohio State University, Columbus, Ohio
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  • Kim L. McBride,

    1. Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    2. Department of Pediatrics, The Ohio State University, Columbus, Ohio
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  • Gail E. Herman

    Corresponding author
    1. Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    2. Department of Pediatrics, The Ohio State University, Columbus, Ohio
    • Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, 700 Children's Drive, Room W403, Columbus, OH 43205
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Abstract

Structural and sequence variation have been described in several members of the contactin (CNTN) and contactin-associated protein (CNTNAP) gene families in association with neurodevelopmental disorders, including autism. Using array comparative genome hybridization (CGH), we identified a maternally inherited ∼535 kb deletion at 3p26.3 encompassing the 5′ end of the contactin 4 gene (CNTN4) in a patient with autism. Based on this finding and previous reports implicating genomic rearrangements of CNTN4 in autism spectrum disorders (ASDs) and 3p microdeletion syndrome, we undertook sequencing of the coding regions of the gene in a local ASD cohort in comparison with a set of controls. Unique missense variants were identified in 4 of 75 unrelated individuals with ASD, as well as in 1 of 107 controls. All of the amino acid substitutions were nonsynonomous, occurred at evolutionarily conserved positions, and were, thus, felt likely to be deleterious. However, these data did not reach statistical significance, nor did the variants segregate with disease within all of the ASD families. Finally, there was no detectable difference in binding of two of the variants to the interacting protein PTPRG in vitro. Thus, additional larger studies will be necessary to determine whether CNTN4 functions as an autism susceptibility locus in combination with other genetic and/or environmental factors.Autism Res2011,4:189–199. © 2011 International Society for Autism Research, Wiley Periodicals, Inc.

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