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19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression

Authors

  • AM Lehman,

    1. Department of Medical Genetics, University of British Columbia
    2. Rare Disease Foundation
    3. Child and Family Research Institute, University of British Columbia
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  • C du Souich,

    1. Department of Medical Genetics, University of British Columbia
    2. Rare Disease Foundation
    3. Child and Family Research Institute, University of British Columbia
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  • D Chai,

    1. Department of Pathology, University of British Columbia
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  • P Eydoux,

    1. Department of Pathology, University of British Columbia
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  • JL Huang,

    1. Department of Medical Genetics, University of British Columbia
    2. Child and Family Research Institute, University of British Columbia
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  • AK Fok,

    1. Department of Medical Genetics, University of British Columbia
    2. Child and Family Research Institute, University of British Columbia
    3. Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
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  • L Avila,

    1. Department of Medical Genetics, University of British Columbia
    2. Child and Family Research Institute, University of British Columbia
    3. Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
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  • J Swingland,

    1. MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom
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  • AD Delaney,

    1. Genome Sciences Centre, University of British Columbia, Vancouver, Canada
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  • B McGillivray,

    1. Department of Medical Genetics, University of British Columbia
    2. Child and Family Research Institute, University of British Columbia
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  • D Goldowitz,

    1. Department of Medical Genetics, University of British Columbia
    2. Child and Family Research Institute, University of British Columbia
    3. Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
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  • B Argiropoulos,

    1. Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
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  • MS Kobor,

    1. Department of Medical Genetics, University of British Columbia
    2. Child and Family Research Institute, University of British Columbia
    3. Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
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  • CF Boerkoel

    Corresponding author
    1. Department of Medical Genetics, University of British Columbia
    2. Rare Disease Foundation
    3. Child and Family Research Institute, University of British Columbia
      Dr Cornelius Boerkoel, Department of Medical Genetics, Children's and Women's Health Centre of British Columbia, University of British Columbia, V6H3N1 Vancouver, Canada.
      Tel.: +1 604 875 2157;
      fax: +1 604 875 2376;
      e-mail: nboerkoel@cfri.ca
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Dr Cornelius Boerkoel, Department of Medical Genetics, Children's and Women's Health Centre of British Columbia, University of British Columbia, V6H3N1 Vancouver, Canada.
Tel.: +1 604 875 2157;
fax: +1 604 875 2376;
e-mail: nboerkoel@cfri.ca

Abstract

Lehman AM, du Souich C, Chai D, Eydoux P, Huang JL, Fok AK, Avila L, Swingland J, Delaney AD, McGillivray B, Goldowitz D, Argiropoulos B, Kobor MS, Boerkoel CF. 19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression.

Up to 90% of individuals affected by Sotos syndrome have a pathogenic alteration of NSD1 (encodes nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1), a histone methyltransferase that functions as both a transcriptional activator and a repressor. Genomic copy number variations may also cause a Sotos-like phenotype. We evaluated a three-generation family segregating a Sotos-like disorder characterized by typical facial features, overgrowth, learning disabilities, and advanced bone age. Affected individuals did not have a detectable NSD1 mutation, but rather were found to have a 1.9 Mb microduplication of 19p13.2 with breakpoints in two highly homologous Alu elements. Because the duplication included the DNA methyltransferase gene (DNMT1), we assessed DNA methylation of peripheral blood and buccal cell DNA and detected no alterations. We also examined peripheral blood gene expression and found evidence for increased expression of genes within the duplicated region. We conclude that microduplication of 19p13.2 is a novel genomic disorder characterized by variable neurocognitive disability, overgrowth, and facial dysmorphism similar to Sotos syndrome. Failed compensation of gene duplication at the transcriptional level, as seen in peripheral blood, supports gene dosage as the cause of this disorder.

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