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

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.

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