Duplication of 7p12.1-p13, including GRB10 and IGFBP1, in a mother and daughter with features of Silver-Russell syndrome

Silver-Russell syndrome (SRS) has been associated with maternal uniparental disomy (UPD) of chromosome 7 in approximately 10% of cases, suggesting tha t at least one imprinted gene on chromosome 7 is involved in the pathogenes is of the disease. We report a proximal 7p interstitial inverted duplicatio n in a mother and daughter both of whom have features of SRS, including mar ked short stature, low birth weight, facial asymmetry and 5th finger clinod actyly. Fluorescence in situ hybridisation (FISH) with YAC probes enabled d elineation of the duplicated region to 7p12.1-p13. This region of proximal chromosome 7 is known to be homologous to an imprinted region in the mouse chromosome 11 and contains the growth-related genes GRB10 (growth factor re ceptor-bound protein 10), EGFR (epidermal growth factor receptor) and IGFBP 1 (insulin-like growth factor binding protein 1), all of which have been su ggested as candidate genes for SRS. Molecular analysis showed that the dupl ication in both mother and daughter spanned a distance of similar to 10 cM and included GRB10 and IGFBP1 but not EGFR. The de novo duplication in the proband's mother was shown to be of paternal origin. In order to test the h ypothesis that sub-microscopic duplications of 7p, whether maternal or pate rnal in origin, are responsible for at least some cases of SRS, we screened a further eight patients referred to our laboratory for SRS. None were fou nd to have duplications of either GRB10 or IGFBP1. The hypothesis that sub- microscopic duplications including GRB10 and IGFBP1 is a cause of SRS remai ns a possibility and warrants further investigation. Importantly, in contra st to current thinking, our results suggest that imprinted genes mag. not u nderlie the SRS phenotype, and we propose an alternative hypothesis to expl ain the occurrence of maternal UPD 7 seen in some cases of SRS.