Chromosome 7p disruptions in Silver Russell syndrome: delineating an imprinted candidate gene region

Silver-Russell syndrome (SRS) is characterised by pre- and postnatal growth restriction (PNGR) and additional dysmorphic features including body asymmetry and fifth finger clinodactyly. The syndrome is genetically heterogeneous, with a number of chromosomes implicated. However, maternal uniparental disomy for chromosome 7 has been demonstrated in up to 10% of all cases. Three SRS probands have previously been described with a maternally inherited duplication of 7p11.2-p13, defining this as a candidate region. Over-expression of a maternally transcribed, imprinted gene with growth-suppressing activity located within the duplicated region, or breakpoint disruption of genes or regulatory sequences, may account for the phenotype in these cases. Here we describe two additional SRS, patients and four probands with PNGR with a range of cytogenetic disruptions of 7p, including duplications, pericentric inversions and a translocation. An incomplete contig consisting of 80 PACs and BACs from the centromere to 7p14 was constructed. Individual clones from this contig were used as FISH probes to map the breakpoints in the six new cases and the three duplication probands previously described. Our data provide further evidence for a candidate SRS region at 7p11.1-p14. A common breakpoint region was identified within 7p11.2 in all nine cases, pinpointing this specific interval. The imprinting status of genes within the 7p11.1-p14 region flanked by the most extreme breakpoints have been analysed using both somatic cell hybrids containing a single full-length maternally or paternally derived chromosome 7 and expressed single nucleotide polymorphisms in paired fetal and maternal samples.