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Silver-Russell syndrome and ring chromosome 7
  1. * Action Research Laboratory for the Molecular Biology of Fetal Development, Division of Paediatrics, Obstetrics and Gynaecology, Imperial College School of Medicine, Queen Charlotte's and Chelsea Hospital, Goldhawk Road, London W6 0XG, UK
  2. Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK
  1. Professor Preece, mpreece{at}

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Editor—We read the recent paper by Miyoshiet al 1 with great interest. They report a child with Silver-Russell syndrome (SRS) and maternal uniparental disomy of chromosome 7 (mUPD7), with 30% mosaicism for an additional ring chromosome 7 of paternal origin. As the ring contained four CA repeat polymorphic markers which map to the region 7p13-q11 (D7S2552, D7S499, D7S494, and D7S2503), they concluded that imprinted genes within this region can be ruled out as candidates for SRS. While the data are interesting, we feel that they are inadequate to support this conclusion.

Firstly, the genetic distance spanned by the four markers used to define the extent of biparental inheritance is small (2.26 cM between 64.81 and 67.07 cM).2 Furthermore, UPD was shown using marker D7S506 which is estimated to lie less than 0.1 cM distal to D7S2552. The trisomic region is therefore likely to be considerably smaller than 7p13-q11. There are now more accurate localisations for at least two of the biparentally inherited markers; D7S499 and D7S494 have been mapped to 7p11.2 and 7p11.2-q11.1, respectively.3 The ring may therefore only include a small region close to the centromere, leaving 7p12-13 uninvolved. It is interesting to note that three genes (IGFBP1, IGFBP3, and GRB10), which have been proposed as candidates for SRS,4 5 lie between two markers (D7S2497 and D7S506) which are outside the potentially excluded region.

There is also no evidence to show that genes on the ring chromosome are active. Indeed, follow up of patients with supernumerary marker chromosomes has found that they are frequently not associated with any phenotypic effect.6 Finally, even if the ring chromosome is active, it can only be used to infer exclusion of a paternally expressed imprinted gene from the region. If the SRS gene is transcribed exclusively from the maternal allele, it will be overexpressed in this patient, whether or not the gene is located within the ring chromosome, since she has mUPD7.

In conclusion, caution should be used not to over-interpret the data reported by Miyoshi et al.1Nevertheless, the findings do support the continuing search for a candidate imprinted gene(s) for SRS on chromosome 7. They also emphasise the importance of searching for cytogenetic abnormalities of chromosome 7 in SRS which will provide much needed clues to the region involved.

 This letter was shown to Dr Miyoshi et al, who reply as follows.

Dr Wakeling et al suggest that the ring chromosome 7 observed in our SRS patient must be smaller than we estimated. This is based on databases1-2 1-3; for example, the genetic distance between markers D7S506 and D7S2552 they cite is <0.1 cM. However, when using another database,1-7 it is calculated to be 1.1 cM. Since this discrepancy is obviously derived from the different databases used, and since not many DNA markers have physically been assigned to the chromosomal region, we tried to perform FISH mapping of D7S506, which is the most centromeric marker among those showing UPD(7)mat in our previous study,1-1 using a PAC clone (303F13) containing the marker as a probe. Consequently, the PAC was mapped to the 7p11.1-p11.2 region. This finding indicates that the four biparentally inherited markers (D7S2552, D7S499, D7S494, and D7S2503) we identified1-1 are located centromerically to D7S506 and the short arm breakpoint of the ring chromosome must lie between them. In addition, FISH analysis using a probe for the elastin gene locus (VYSIS, UK) that was localised to 7q11.23 gave no fluorescence signals on the ring chromosome. Therefore, the extent of the ring is smaller than the 7p11.2-q11.23 segment.


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