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Silver-Russell syndrome (SRS) is characterised by pre- and postnatal growth restriction in association with other clinically recognised dysmorphic features such as triangular facies, asymmetry, and fifth finger clinodactyly.1–3 Since the major diagnostic features involve reduced growth, it is tempting to postulate that altered expression of a protein within a growth factor cascade may be causative.
There have been numerous documented defects of genes coding for proteins in the insulin-like growth factor (IGF) signalling pathways, whether the receptors, ligands, or signal modulators, which result in a SRS-like phenotype. Probands with ring chromosomes or deletions involving the 15q26-qter region present with growth failure and SRS-like features.4–11 It has been proposed that the phenotypes are the result of hemizygosity at the IGF1 receptor (IGF1R) gene. We have shown, however, that hemizygosity at this locus is not a common cause of SRS.9,11 In addition, it has been well documented that maternal uniparental disomy (UPD) of chromosome 7 is present in approximately 10% of SRS cases13–16 and no consistent regions of isodisomy have been shown for the full length of the chromosome.17 This suggests that there are imprinted genes on chromosome 7, which when disrupted are responsible for the phenotype. Recently two independently reported candidate gene regions on chromosome 7 containing imprinted genes defined by cytogenetic disruptions in SRS probands have been reported. Two unrelated probands with maternally transmitted duplications of 7p11.2-p13 define the first region.10,18 Recently, a number of other cytogenetic disruptions including balanced translocations and inversions within this region have been described in association with the SRS or SRS-like phenotype19 (Monk et al, manuscript submitted). This candidate gene region contains the growth related genes insulin-like growth factor binding proteins 1 and 3 (IGFBPs) and growth factor binding protein 10 …