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

Abstract

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.

Diagnosis and management of Silver–Russell syndrome: first international consensus statement

“…In addition, the duplication of pre-existing pathogenic mutations by isodisomy can lead to the clinical expression of recessive disorders (such as cystic fibrosis) in patients with upd(7)mat [38][39][40] . Candidate SRS regions have been suggested through identification of patients with segmental upd(7)mat or CNVs (see Supplementary information S3 (table)); the primary candidate SRS genes on chromosome 7 are currently GRB10 (7p12.1) and MEST (7q32) [41][42][43][44][45][46][47][48] . Microsatellite analysis was the first diagnostic test for upd(7)mat 35,36 ; however, this analysis cannot detect imprinting defects (epimutations) and requires DNA from at least one parent.…”

Mitochondrial ribosomal proteins: Candidate genes for mitochondrial disease

“…1 As inferred earlier, mitochondrial disorders can manifest in various phenotypic classifications. We see in Tables 1 and 2 that MRP genes are candidates for dwarfism, growth retardation, and limb deformity disorders such as Russell-Silver Syndrome, 49,50 Stuve-Wiedemann Syndrome, 51 and Moebius Syndrome I. 52 Metabolic disorders for which MRP genes associate by map position are Multiple Mitochondrial Dysfunctions, 53 Stuve-Wiedemann Syndrome, 51 Leigh Syndrome, 54 and diabetes.…”

Differential expression of imprinted genes in normal and IUGR human placentas

“…14 The role of genomic imprinting in IUGR pregnancies has been investigated, but systematic studies are sparse. 15,16 A recent study comparing gene expression profiles of normal and IUGR placentas using microarrays which included 27 imprinted genes demonstrated that 22% of the imprinted genes were differentially expressed, far in excess of the non-imprinted genes. 7 These results strongly demonstrate a critical role of genomic imprinting in placental/fetal growth and suggest that IUGR may be a result of altered expression of critical imprinted genes.…”