title: Genomic imbalance in the centromeric 11p15 imprinting center in three families: Further evidence of a role for IC2 as a cause of Russell-Silver syndrome.
abstract: Russell-Silver syndrome is a heterogeneous disorder characterized by intrauterine growth retardation, postnatal growth deficiency, characteristic facial appearance, and other variable features. Genetic and epigenetic alterations are identified in about 60% of individuals with Russell-Silver syndrome. Most frequently, Russell-Silver syndrome is caused by altered gene expression on chromosome 11p15 due to loss of methylation at the telomeric imprinting center. To date there have been a handful of isolated clinical reports implicating the centromeric imprinting center 2 in the etiology of Russell-Silver syndrome. Here we report three new families with genomic imbalances, involving imprinting center 2 resulting in gain of methylation at this center and a Russell-Silver syndrome phenotype, including two families with a maternally inherited microduplication and the first pediatric patient with a paternally derived microdeletion. The findings in our families provide additional evidence of a role for imprinting center 2 in the etiology of Russell-Silver syndrome and suggest that imprinting center 2 imprinting abnormalities may be a more common cause of Russell-Silver syndrome than previously recognized. Furthermore, our findings together with previous clinical reports of genomic imbalances involving imprinting center 2 serve to underscore the complexity of the epigenetic regulation of the 11p15 region making it challenging to predict phenotype on the basis of genotype alone. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Division of Clinical & Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Cytrynbaum
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Pediatrics and Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Chong
authors.affiliation: Division of Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Vickie
authors.initials: V
authors.lastname: Hannig
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Sanaa
authors.initials: S
authors.lastname: Choufani
authors.affiliation: Division of Clinical & Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Shuman
authors.affiliation: Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Leslie
authors.initials: L
authors.lastname: Steele
authors.affiliation: Division of Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Thomas
authors.initials: T
authors.lastname: Morgan
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.|Paediatric Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Dimitri J
authors.initials: DJ
authors.lastname: Stavropoulos
authors.affiliation: Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.|Paediatric Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Raveen K
authors.initials: RK
authors.lastname: Basran
authors.affiliation: Division of Clinical & Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada. rweksb@sickkids.ca.|Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. rweksb@sickkids.ca.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. rweksb@sickkids.ca.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. rweksb@sickkids.ca.|Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. rweksb@sickkids.ca.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
mesh_terms: D002503:Centromere / Q000235:genetics*; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D018392:Genomic Imprinting; D006801:Humans; D007223:Infant; D008297:Male; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D056730:Silver-Russell Syndrome / Q000175:diagnosis* / Q000235:genetics*
keywords: CDKN1C; DNA methylation; IC2; Russell-Silver syndrome; microdeletion; microduplication