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Silver–Russell syndrome (SRS) (OMIM 180860) has been recognised as a clinical entity since the 1950s; however, a molecular genetic cause remained unknown until 1997 when maternal uniparental disomy for chromosome 7 (mUPD7) was found in approximately 10% of affected individuals. The focus then turned to the identification of causative imprinted genes on chromosome 7. Over the next 10 years many of the potential candidate genes identified on chromosome 7 as well as many imprinted loci elsewhere were excluded.1–13 However, in 2006, Gicquel et al identified a major role in the aetiology of SRS for the chromosome 11p15.5 region.14–16 This work, and a succession of comparative, detailed and confirmatory studies, demonstrated an epigenetic signature of hypomethylation at the 11p15.5 imprinting control region 1 (ICR1) in 30–60% of SRS probands (table 1). Here the H19 differentially methylated domain (H19 DMD) regulates the methylation and therefore respective maternal or paternal expression of H19 and insulin-like growth factor 2 (IGF2) genes.
Hypomethylation at ICR1 causes epigenetic dysregulation of H19 and IGF2, ultimately resulting in reduced expression of IGF2 and potentially phenotypic growth restriction. Interestingly, the degree of hypomethylation was also found to correlate with the severity of the growth phenotype as well as additional SRS diagnostic features. In comparison, patients with mUPD7 were clinically distinguishable displaying a noticeably milder phenotype.
Since then, the literature includes a number of detailed clinical evaluations with the aim of developing a clinical scoring system to help characterise specific subgroups of SRS caused by mUPD7, hypomethylation of 11p15.5 or those with an …
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