Mosaicism for genome-wide paternal uniparental disomy with features of multiple imprinting disorders: Diagnostic and management issues

Authors

  • Michal Inbar-Feigenberg,

    1. Program in Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
    2. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
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    • Michal Inbar-Feigenberg and Sanaa Choufani contributed equally to the work.

  • Sanaa Choufani,

    1. Program in Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
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    • Michal Inbar-Feigenberg and Sanaa Choufani contributed equally to the work.

  • Cheryl Cytrynbaum,

    1. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
    2. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
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  • Yi-An Chen,

    1. Program in Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
    2. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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  • Leslie Steele,

    1. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
    2. Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
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  • Cheryl Shuman,

    1. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
    2. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
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  • Peter N. Ray,

    1. Program in Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
    2. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
    3. Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
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  • Dr. Rosanna Weksberg

    Corresponding author
    1. Program in Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
    2. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
    3. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
    4. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
    • Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada M5G 1X8.
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  • None of the authors would like to declare a conflict of interest.

  • How to Cite this Article: Inbar-Feigenberg M, Choufani S, Cytrynbaum C, Chen Y, Steele L, Shuman C, Ray P, Weksberg R. 2012. Mosaicism for genome-wide paternal uniparental disomy with features of multiple imprinting disorders: Diagnostic and management issues. Am J Med Genet Part A 161A:13–20.

Abstract

Mosaicism for genome-wide paternal uniparental disomy (UPD) has been reported in only seven live born individuals to date. Clinical presentation includes manifestations of multiple paternal UPD syndromes with high variability, likely due to the variable levels of mosaicism in different somatic tissues. We report an eighth case in a female patient with mosaicism for genome-wide paternal UPD which highlights the complex clinical presentation. Our patient had features of Beckwith–Wiedemann syndrome (BWS), Angelman syndrome, and congenital hyperinsulinism. The clinical findings included prematurity, organomegaly, hemihyperplasia, developmental delay, benign tumors, and cystic lesions. The diagnosis in our patient was established utilizing microarray-based genome-wide DNA methylation analysis performed on leukocyte DNA. Targeted multiplex ligation-dependent probe amplification (MLPA) analysis of chromosome regions 11p15 and 15q13 confirmed mosaicism for paternal UPD at these genomic regions. This case represents the first report of microarray-based genome-wide DNA methylation analysis in the diagnosis of genome-wide paternal UPD. The application of microarray-based genome-wide DNA methylation analysis on selected individuals with complex clinical presentations could be a valuable diagnostic tool to improve the detection rate of mosaic genome-wide paternal UPD. This approach, which screens many loci simultaneously, is more cost-effective and less labor-intensive than performing multiple targeted DNA methylation-based assays. Identification of individuals with mosaicism for genome-wide paternal UPD is an important goal as it confers a low recurrence risk for the family and identifies individuals who require surveillance due to increased tumor risk. © 2012 Wiley Periodicals, Inc.

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