RESEARCH ARTICLE Screening of DNA Methylation at the H19 Promoter or the Distal Region of its ICR1 Ensures Efficient Detection of Chromosome 11p15 Epimutations in Russell–Silver Syndrome Shin-Ichi Horike, 1,2 Jose Carlos P. Ferreira, 1,3 Makiko Meguro-Horike, 1,2 Sanaa Choufani, 1 Adam C. Smith, 1,3 Cheryl Shuman, 1,4,5 Wendy Meschino, 6 David Chitayat, 1,4,5 Elaine Zackai, 7 Stephen W. Scherer, 1 and Rosanna Weksberg 1,3,4,5 * 1 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada 2 Frontier Science Organization, Institute for Gene Research, Kanazawa University, Kanazawa, Japan 3 Institute of Medical Sciences, University of Toronto, Toronto, Canada 4 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada 5 Department of Molecular Genetics, University of Toronto, Toronto, Canada 6 Genetics, North York General Hospital, Toronto, Canada 7 Division of Human Genetics & Molecular Biology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Received 26 November 2008; Accepted 17 July 2009 Over a 10-year period blood samples were collected from 57 individuals with growth restriction and RSS-like features. Our goal was to identify epigenetic abnormalities in this cohort, including uniparental disomy of chromosome 7 (UPD7), meth- ylation changes at chromosome11p15, as well as new epigenomic alterations. We evaluated the methylation status of 7 imprinting control regions on chromosomes 7, 11, 14, and 15. UPD7 and chromosome 7 structural abnormalities had been previously identified in five patients. Epigenetic alterations on chromosome 11p15 were identified in 11 patients. Of interest, in 3 of these 11 patients, the epigenetic alterations were limited to the H19 promoter and the distal region of its associated imprinting center, ICR1. In addition, in one patient, we detected methyla- tion changes consistent with maternal UPD at all tested im- printed regions. This patient series suggests that epimutations on chromosome 11p15 can be most efficiently detected in RSS patients by screening for DNA methylation defects at the H19 promoter or the distal region of ICR. Ó 2009 Wiley-Liss, Inc. Key words: Russell–Silver syndrome; H19; DNA methylation; genomic imprinting; maternal UPD INTRODUCTION Russell–Silver syndrome (RSS) (OMIM 180860), is a clinically and genetically heterogeneous disorder usually diagnosed in children with prenatal and postnatal growth restriction, a relatively large head circumference, dysmorphic facial features and body asymme- try [Silver et al., 1953; Russell, 1954]. The majority of RSS patients Additional supporting information may be found in the online version of this article. Grant sponsor: Genome Canada/Ontario Genomics Institute; Grant sponsor: Howard Hughes Medical Institute (HHMI); Grant sponsor: McLaughlin Centre for Molecular Medicine; Grant sponsor: The Centre for Applied Genomics; Grant sponsor: Fundac ¸~ ao para a Ci ^ encia e Tecnologia, Lisbon, Portugal. Shin-Ichi Horike and Jose Carlos P. Ferreira contributed equally to this work. *Correspondence to: Dr. Rosanna Weksberg, Clinical and Metabolic Genetics, The Hospital for Sick Children, University Ave., Toronto, Ontario, Canada M5G 1X8. E-mail: rweksb@sickkids.ca Published online 26 October 2009 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/ajmg.a.33065 How to Cite this Article: Horike S-I, Ferreira JCP, Meguro-Horike M, Choufani S, Smith AC, Shuman C, Meschino W, Chitayat D, Zackai E, Scherer SW, Weksberg R. 2009. Screening of DNA methylation at the H19 promoter or the distal region of its ICR1 ensures efficient detection of chromosome 11p15 epimutations in Russell–Silver syndrome. Am J Med Genet Part A 149A:2415–2423. Ó 2009 Wiley-Liss, Inc. 2415