Duplication of 7p11.2-p13, including GRB10, in Silver-Russell syndrome

Silver-Russell syndrome (SRS) is characterized by pre-and postnatal growth failure and other dysmorphic features. The syndrome is genetically heteroge nous, but maternal uniparental disomy of chromosome 7 has been demonstrated in similar to 7% of cases. This suggests that at least one gene on chromos ome 7 is imprinted and involved in the pathogenesis of SRS. We have identif ied a de novo duplication of 7p11.2-p13 in a proband with features characte ristic of SRS. FISH confirmed the presence of a tandem duplication encompas sing the genes for growth factor receptor-binding protein 10 (GRB10) and in sulinlike growth factor-binding proteins 1 and 3 (IGFBP1 and -3) but not th at for epidermal growth factor-receptor (EGFR). Microsatellite markers show ed that the duplication was of maternal origin. These findings provide the first evidence that SRS may result from overexpression of a maternally expr essed imprinted gene, rather than from absent expression of a paternally ex pressed gene. GRB10 lies within the duplicated region and is a strong candi date, since it is a known growth supressor. Futhermore, the mouse homologue (Gub10/Meg1) is reported to be maternally expressed and maps to the imprin ted region of proximal mouse chromosome 11 that demonstrates prenatal growt h failure when it is maternally disomic. We have demonstrated that the GRB1 0 genomic interval replicates asynchronously in human lymphocytes, suggesti ve of imprinting. An additional 36 SRS probands were investigated for dupli cation of GRB10, but none were found. However, it remains possible that GRB 10 and/or other genes within 7p11.2-p13 are responsible for some cases of S RS.