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

Am J Med Genet A. 2016 Oct;170(10):2731-9. doi: 10.1002/ajmg.a.37819. Epub 2016 Jul 4.


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.

Keywords: CDKN1C; DNA methylation; IC2; Russell-Silver syndrome; microdeletion; microduplication.

MeSH terms

  • Centromere / genetics*
  • Chromosome Mapping
  • Chromosomes, Human, Pair 11*
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations
  • DNA Methylation
  • Facies
  • Female
  • Genetic Association Studies
  • Genomic Imprinting*
  • Humans
  • Infant
  • Male
  • Pedigree
  • Phenotype
  • Sequence Analysis, DNA
  • Silver-Russell Syndrome / diagnosis*
  • Silver-Russell Syndrome / genetics*