Hypomethylation of a centromeric block of ICR1 is sufficient to cause Silver-Russell syndrome.

Abstract

Silver-Russell syndrome (SRS) is a representative imprinting disorder. A major cause is the loss of methylation (LOM) of imprinting control region 1 (ICR1) within the <i>IGF2/H19</i> domain. ICR1 is a gametic differentially methylated region (DMR) consisting of two repeat blocks, with each block including three CTCF target sites (CTSs). ICR1-LOM on the paternal allele allows CTCF to bind to CTSs, resulting in <i>IGF2</i> repression on the paternal allele and biallelic expression of <i>H19</i> We analysed 10 differentially methylated sites (DMSs) (ie, seven CTSs and three somatic DMRs within the <i>IGF2/H19</i> domain, including two <i>IGF2</i>-DMRs and the <i>H19</i>-promoter) in five SRS patients with ICR1-LOM. Four patients showed consistent hypomethylation at all DMSs; however, one exhibited a peculiar LOM pattern, showing LOM at the centromeric region of the <i>IGF2</i>/<i>H19</i> domain but normal methylation at the telomeric region. This raised important points: there may be a separate regulation of DNA methylation for the two repeat blocks within ICR1; there is independent control of somatic DMRs under each repeat block; sufficient <i>IGF2</i> repression to cause SRS phenotypes occurs by LOM only in the centromeric block; and the need for simultaneous methylation analysis of several DMSs in both blocks for a correct molecular diagnosis.