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Clinical and molecular characterization of duplications encompassing the human SHOX gene reveal a variable effect on stature

Authors

  • N. Simon Thomas,

    Corresponding author
    1. Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK
    2. Human Genetics, University of Southampton, Southampton, UK
    • Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
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  • John F. Harvey,

    1. Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK
    2. National Genetics Reference Laboratory (Wessex), Salisbury District Hospital, Salisbury, UK
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  • David J. Bunyan,

    1. Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK
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  • Julia Rankin,

    1. Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
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  • Giedre Grigelioniene,

    1. Clinical Genetics, Karolinska University Hospital Solna, Stockholm, Sweden
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  • Damien L. Bruno,

    1. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Melbourne, Australia
    2. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Melbourne, Australia
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  • Tiong Y. Tan,

    1. Genetic Health Services Victoria, Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Parkville, Melbourne, Australia
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  • Susan Tomkins,

    1. Department of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, St Michael's Hospital, Southwell Street, Bristol, UK
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  • Robert Hastings

    1. Department of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, St Michael's Hospital, Southwell Street, Bristol, UK
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  • How to cite this article: Thomas NS, Harvey JF, Bunyan DJ, Rankin J, Grigelioniene G, Bruno DL, Tan TY, Tomkins S, Hastings R. 2009. Clinical and molecular characterization of duplications encompassing the human SHOX gene reveal a variable effect on stature. Am J Med Genet Part A 149A:1407–1414.

Abstract

Deletions of the SHOX gene are well documented and cause disproportionate short stature and variable skeletal abnormalities. In contrast interstitial SHOX duplications limited to PAR1 appear to be very rare and the clinical significance of the only case report in the literature is unclear. Mapping of this duplication has now shown that it includes the entire SHOX gene but little flanking sequence and so will not encompass any of the long-range enhancers required for SHOX transcription. We now describe the clinical and molecular characterization of three additional cases. The duplications all included the SHOX coding sequence but varied in the amount of flanking sequence involved. The probands were ascertained for a variety of reasons: hypotonia and features of Asperger syndrome, Leri–Weill dyschondrosteosis (LWD), and a family history of cleft palate. However, the presence of a duplication did not correlate with any of these features or with evidence of skeletal abnormality. Remarkably, the proband with LWD had inherited both a SHOX deletion and a duplication. The effect of the duplications on stature was variable: height appeared to be elevated in some carriers, particularly in those with the largest duplications, but was still within the normal range. SHOX duplications are likely to be under ascertained and more cases need to be identified and characterized in detail in order to accurately determine their phenotypic consequences. © 2009 Wiley-Liss, Inc.

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