RESEARCH ARTICLE Mosaicism for Genome-Wide Paternal Uniparen Disomy With Features of Multiple Imprinting Disorders: Diagnostic and Management Issues Michal Inbar-Feigenberg, 1,2,# Sanaa Choufani, 1,# Cheryl Cytrynbaum, 2,3 Yi-An Chen, 1,4 Leslie Steele, 3,5 Cheryl Shuman, 2,3 Peter N. Ray, 1,3,5 and Rosanna Weksberg 1,2,3,4 * 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 5 Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada Manuscript Received: 27 January 2012; Manuscript Accepted: 13 August 2012 Mosaicism forgenome-widepaternaluniparentaldisomy (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 variablelevelsof mosaicism in differentsomatictissues. We report an eighth case in a female patient with mosaicism for genome-wide paternal UPD which highlights the complex clinicalpresentation. Our patienthad features of Beckwith– Wiedemannsyndrome(BWS), Angelmansyndrome,and congenitalhyperinsulinism. The clinical findingsincluded prematurity, organomegaly, hemihyperplasia, developmental delay,benign tumors, and cystic lesions. The diagnosis in our patient was established utilizing microarray-based genome-wide DNA methylation analysisperformed on leukocyteDNA. Targeted multiplex ligation-dependent probe amplification (MLPA) analysis of chromosome regions 11p15 and 15q13 con- firmed 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 simulta- neously,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 sur- veillance due to increased tumor risk. 2012 Wiley Periodicals, Inc. Key words: mosaic genome-wide paternal uniparental disomy; Beckwith–Wiedemann syndrome; epigenetics; genomic imprint- ing; DNA methylation; Illumina microarray; MS-MLPA INTRODUCTION Mosaic genome-wide paternal uniparental disomy (UPD) reported in few live born individuals. It is characterized b mosaicism of a normal cellline and a second cell line with two paternal copies of all chromosomes and no maternal hom An androgenetic conceptus, carrying two paternal genom maternal genome in all cells, fails to drive embryonic/feta ment and results in a hydatidiform mole (AnCHM). Such a None of the authors would like to declare a conflict of interest. # Michal Inbar-Feigenberg and Sanaa Choufani contributed equa work. *Correspondence to: Dr. Rosanna Weksberg, Division of Clinical and Metabolic Gene Hospital for Sick Children, Toronto, ON, Canada M5G 1X8. E-mail: rweksb@sickkids.ca Article first published online in Wiley Online Library (wileyonlinelibrary.com): 13 December 2012 DOI 10.1002/ajmg.a.35651 How to Cite this Article: Inbar-Feigenberg M, Choufani S, Cytrynbaum C, Chen Y, Steele L, Shuman C, Ray P, Weksberg R. 2013. 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. 2012 Wiley Periodicals, Inc. 13