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Cerebellar and posterior fossa malformations in patients with autism-associated chromosome 22q13 terminal deletion

Authors

  • Kimberly A. Aldinger,

    1. Committee on Neurobiology, The University of Chicago, Chicago, Illinois
    Current affiliation:
    1. Zilkha Neurogenetic Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA.
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  • Jillene Kogan,

    1. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
    Current affiliation:
    1. Department of Cytogenetics, ACL Laboratories, Rosemont, IL.
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  • Virginia Kimonis,

    1. Department of Pediatrics, University of California, Irvine, Orange, California
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  • Bridget Fernandez,

    1. Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
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  • Denise Horn,

    1. Institut fuer Medizinische Genetik und Humangenetik, Charite Universitatsmedizin, Berlin, Germany
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  • Eva Klopocki,

    1. Institut fuer Medizinische Genetik und Humangenetik, Charite Universitatsmedizin, Berlin, Germany
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  • Brian Chung,

    1. Division of Clinical and Metabolic Genetics, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Annick Toutain,

    1. Genetics Department, Hospital Bretonneau, University Hospital of Tours, Tours, France
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  • Rosanna Weksberg,

    1. Division of Clinical and Metabolic Genetics, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Kathleen J. Millen,

    1. Division of Genetic Medicine, Department of Pediatrics, Center for Integrative Brain Research, Seattle Children's Research Institute, University of Washington, Seattle, Washington
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  • A. James Barkovich,

    1. Departments of Neurology, Pediatrics and Radiology, University of California, San Francisco, California
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  • Dr. William B. Dobyns

    Corresponding author
    1. Division of Genetic Medicine, Department of Pediatrics, Center for Integrative Brain Research, Seattle Children's Research Institute, University of Washington, Seattle, Washington
    • Seattle Children's Research Institute, Center for Integrative Brain Research, 1900 Ninth Avenue, Seattle, WA 98101.
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  • The authors declare no conflict of interest.

  • How to Cite this Article: Aldinger KA, Kogan J, Kimonis V, Fernandez B, Horn D, Klopocki E, Chung B, Toutain A, Weksberg R, Millen KJ, Barkovich AJ, Dobyns WB. 2012. Cerebellar and posterior fossa malformations in patients with autism-associated chromosome 22q13 terminal deletion. Am J Med Genet Part A 161A:131–136.

Abstract

The 22q13.3 deletion causes a neurodevelopmental syndrome, also known as Phelan-McDermid syndrome (MIM #606232), characterized by developmental delay and severe delay or absence of expressive speech. Two patients with hemizygous chromosome 22q13.3 telomeric deletion were referred to us when brain-imaging studies revealed cerebellar vermis hypoplasia (CBVH). To determine whether developmental abnormalities of the cerebellum are a consistent feature of the 22q13.3 deletion syndrome, we examined brain-imaging studies for 10 unrelated subjects with 22q13 terminal deletion. In seven cases where the availability of DNA and array technology allowed, we mapped deletion boundaries using comparative intensity analysis with single nucleotide polymorphism (SNP) microarrays. Approximate deletion boundaries for three additional cases were derived from clinical or published molecular data. We also examined brain-imaging studies for a patient with an intragenic SHANK3 mutation. We report the first brain-imaging data showing that some patients with 22q13 deletions have severe posterior CBVH, and one individual with a SHANK3 mutation has a normal cerebellum. This genotype–phenotype study suggests that the 22q13 deletion phenotype includes abnormal posterior fossa structures that are unlikely to be attributed to SHANK3 disruption. Other genes in the region, including PLXNB2 and MAPK8IP2, display brain expression patterns and mouse mutant phenotypes critical for proper cerebellar development. Future studies of these genes may elucidate their relationship to 22q13.3 deletion phenotypes. © 2012 Wiley Periodicals, Inc.

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