M A Preece

The spectrum of Silver-Russell syndrome : a clinical and molecular genetic study and new diagnostic criteria

The Silver-Russell syndrome (SRS) is characterised by severe intrauterine growth retardation, with a preserved head circumference, leading to a lean body habitus and short stature. Facial dysmorphism and asymmetry are considered typical features of the syndrome, although the range of phenotypic variance is unknown. Fifty seven subjects varying in age from 0.84 to 35.01 years, in whom the diagnosis of SRS had been considered definite or likely, were re-evaluated in a combined clinical and molecular study by a single observer (SMP). u2003In 50 patients the clinical findings complied with a very broad definition of SRS. Notable additional findings included generalised camptodactyly seen in 11 (22%), many with distal arthrogryposis. Thirteen of the 25 males required genital surgery for conditions including hypospadias and inguinal hernia. u2003Fourteen (36.8%) subjects above school age have received a statement of special educational needs. u2003Molecular genetic analysis was performed in 42 subjects and has identified maternal uniparental disomy of chromosome 7 in four. The phenotype was generally milder with birth weights for one patient above and three below −2 SD from the mean. Two children had classical facial dysmorphic features, and two had a milder facial phenotype. Of relevance to the possible molecular mechanism underlying this condition, none of the four disomic patients had significant asymmetry.

The genetic aetiology of Silver-Russell syndrome

Silver–Russell syndrome (SRS MIM180860) is a disorder characterised by intrauterine and/or postnatal growth restriction and typical facies. However, the clinical picture is extremely diverse due to numerous diagnostic features reflecting a heterogeneous genetic disorder. The mode of inheritance is variable with sporadic cases also being described. Maternal uniparental disomy (mUPD) of chromosome 7 accounts for 10% of SRS cases and many candidate imprinted genes on 7 have been investigated. Chromosome 11 has moved to the forefront as the key chromosome in the aetiology, with reports of methylation defects in the H19 imprinted domain associated with the phenotype in 35–65% of SRS patients. Methylation aberrations have been described in a number of other imprinted growth related disorders such as Beckwith–Wiedmann syndrome. This review discusses these recent developments as well as the previous work on chromosome 7. Other candidate genes/chromosomal regions previously investigated are tabled.

Maternal uniparental disomy 7 in Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is characterised by intrauterine and postnatal growth failure accompanied by a variable number of dysmorphic features. It is usually sporadic although a few familial cases have been described. In a prospective study of 33 patients with sporadic SRS, we have studied the parent of origin of chromosome 7 using variable number tandem repeat (VNTR) or microsatellite repeat markers and have identified two patients with maternal uniparental disomy of chromosome 7 (mUPD7). In one family, inconsistent inheritance of paternal alleles of markers on chromosomes other than 7 led to their exclusion from further study. The probands were clinically mild and symmetrical, but showed no gross clinical differences from the 30 patients with chromosome 7 derived from both parents.

Silver-Russell syndrome: a dissection of the genetic aetiology and candidate chromosomal regions

The main features of Silver-Russell syndrome (SRS) are pre- and postnatal growth restriction and a characteristic small, triangular face. SRS is also accompanied by other dysmorphic features including fifth finger clinodactyly and skeletal asymmetry. The disorder is clinically and genetically heterogeneous, and various modes of inheritance and abnormalities involving chromosomes 7, 8, 15, 17, and 18 have been associated with SRS and SRS-like cases. However, only chromosomes 7 and 17 have been consistently implicated in patients with a strict clinical diagnosis of SRS. Two cases of balanced translocations with breakpoints in 17q23.3-q25 and two cases with a hemizygous deletion of the chorionic somatomammatropin gene (CSH1) on 17q24.1 have been associated with SRS, strongly implicating this region. Maternal uniparental disomy for chromosome 7 (mUPD(7)) occurs in up to 10% of SRS patients, with disruption of genomic imprinting underlying the disease status in these cases. Recently, two SRS patients with a maternal duplication of 7p11.2-p13, and a single proband with segmental mUPD for the region 7q31-qter, were described. These key patients define two separate candidate regions for SRS on both the p and q arms of chromosome 7. Both the 7p11.2-p13 and 7q31-qter regions are subject to genomic imprinting and the homologous regions in the mouse are associated with imprinted growth phenotypes. This review provides an overview of the genetics of SRS, and focuses on the newly defined candidate regions on chromosome 7. The analyses of imprinted candidate genes within 7p11.2-p13 and 7q31-qter, and gene candidates on distal 17q, are discussed.

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.

Maternal repression of the human GRB10 gene in the developing central nervous system; evaluation of the role for GRB10 in Silver-Russell syndrome

The GRB10 gene encodes a growth suppressor and maps to human chromosome 7p11.2-p13. Maternal duplication (matdup) of this region has recently been associated with Silver-Russell syndrome (SRS), which is characterised by pre- and postnatal growth restriction, craniofacial dysmorphism and lateral asymmetry. Maternal uniparental disomy for chromosome 7 (mUPD7) occurs in approximately 7% of SRS patients. Exposure of a recessive allele due to isodisomy has been ruled out in five mUPD7 cases, suggesting genomic imprinting as the basis for disease. Assuming SRS patients with matdup of 7p11.2-p13 and mUPD7 share a common aetiology, this would implicate a maternally expressed gene from this interval, which is involved in growth inhibition. Murine Grb10 was identified as a maternally expressed gene by subtractive hybridisation using normal and androgenetic mouse embryos. Grb10 maps to the homologous region of proximal mouse chromosome 11, for which mUPD incurs reduced birthweight. A role for GRB10 in SRS was evaluated by determining its imprinting status in multiple human foetal tissues using expressed polymorphisms, and by screening the coding region for mutations in 18 classic non-mUPD7 SRS patients. Maternal repression of GRB10 was observed specifically in the developing central nervous system including brain and spinal cord, with biallelic expression in peripheral tissues. This is in contrast to mouse Grb10, and represents the first example of opposite imprinting in human and mouse homologues. While a role for GRB10 in mUPD7 SRS cases can not be ruled out on the basis of imprinting status, no mutations were identified in the patients screened.

An analysis of the distribution of hetero- and isodisomic regions of chromosome 7 in five mUPD7 Silver-Russell syndrome probands

Silver-Russell syndrome (SRS) shares common features of intrauterine growth retardation (IUGR) and a number of dysmorphic features including lateral asymmetry in about 50% of subjects. Its genetic aetiology is complex and most probably heterogeneous. Approximately 7% of patients with SRS have been found to have maternal uniparental disomy of chromosome 7 (mUPD7). Genomic DNA samples from five SRS patients with mUPD7 have been analysed for common regions of isodisomy using 40 polymorphic markers distributed along the length of chromosome 7. No regions of common isodisomy were found among the five patients. It is most likely that imprinted gene(s) rather than recessive mutations cause the common phenotype. Heterodisomy of markers around the centromere indicated that the underlying cause of the mUPD7 is a maternal meiosis I non-disjunction error in these five subjects.

The imprinted region on human chromosome 7q32 extends to the carboxypeptidase A gene cluster: an imprinted candidate for Silver-Russell syndrome

Imprinted gene(s) on human chromosome 7q32-qter have been postulated to be involved in intrauterine growth restriction associated with Silver-Russell syndrome (SRS) as 7–10% of patients have mUPD(7). Three imprinted genes, MEST, MESTIT1, and COPG2IT1 on chromosome 7q32, are unlikely to cause SRS since epigenetic and sequence mutation analyses have not shown any changes. One hundred kilobases proximal to MEST lies a group of four carboxypeptidase A (CPA) genes. Since most imprinted genes are found in clusters, this study focuses on analysing these CPAs for imprinting effects based on their proximity to an established imprinted domain. Firstly, a replication timing study across 7q32 showed that an extensive genomic region including the CPAs, MEST, MESTIT1, and COPG2IT1 replicates asynchronously. Subsequently, SNP analysis by sequencing RT-PCR products of CPA1, CPA2, CPA4, and CPA5 indicated preferential expression of CPA4. Pyrosequencing was used as a quantitative approach, which confirmed predominantly preferential expression of the maternal allele and biallelic expression in brain. CPA5 expression levels were too low to allow reliable evaluation of allelic expression, while CPA1 and CPA2 both showed biallelic expression. CPA4 was the only gene from this family in which an imprinting effect was shown despite the location of this family of genes next to an imprinted cluster. As CPA4 has a potential role in cell proliferation and differentiation, two preferentially expressed copies in mUPD patients with SRS syndrome would result in excess expression and could alter the growth profiles of these subjects and give rise to intrauterine growth restriction.

Genomic imprinting of PPP1R9A encoding neurabin I in skeletal muscle and extra-embryonic tissues

Genomic imprinting is a phenomenon whereby genes are differentially expressed according to their parental origin.1,2 Mutations which affect the epigenetic states of imprinted domains underlie a number of diseases, including developmental abnormalities, malignant tumours, and psychiatric diseases.3 To date, >50 imprinted genes have been identified in human and mouse (www.otago.ac.nz/IGC). For some genes, imprinting has been shown to be tissue specific4–9 and/or developmentally regulated.10,11 For others, polymorphic imprinting (the term for the imprinting of a gene that is variable between individuals) has also been observed.12,13 These variations in gene expression are considered to be a source of phenotypic heterogeneity in human disease with parent-of-origin effects.4nnThree imprinted loci have been identified on human chromosome 7.14 One of the loci is located on 7q21.3 and two genes, SGCE and PEG10 , are known to be imprinted (fig 1A). Initially the mouse Sgce gene (encoding sarcoglycan-epsilon) was identified as a maternally imprinted (paternally expressed) gene in a subtractive screening experiment using cDNA libraries derived from parthenogenetic and wild-type fibroblast lines.15 The human SGCE gene has also been confirmed to be imprinted.16–18 PEG10 (paternally expressed gene 10), which is immediately telomeric to SGCE , was also shown to be imprinted in embryonic villi.19 Moreover, the mouse Asb4 gene (ankyrin repeat and SOCS box-containing protein 4), which is 800 kb telomeric to Sgce , was found to be maternally expressed by cDNA micro-array based high-throughput screening for genes differentially expressed between mouse parthenogenetic and androgenetic embryos.6 The imprinting status of the human ASB4 and other genes adjacent to SGCE/PEG10 has not yet been determined, but systematic imprinting analyses of mouse genes indicate that the 1 Mb interval encompassing Sgce / Peg10 is part of a large imprinted locus; …

Characterisation of the growth regulating gene IMP3, a candidate for Silver-Russell syndrome

Silver-Russell syndrome (SRS) is characterised by pre- and postnatal growth restriction in association with other clinically recognised dysmorphic features such as triangular facies, asymmetry, and fifth finger clinodactyly.1–3 Since the major diagnostic features involve reduced growth, it is tempting to postulate that altered expression of a protein within a growth factor cascade may be causative.nnThere have been numerous documented defects of genes coding for proteins in the insulin-like growth factor (IGF) signalling pathways, whether the receptors, ligands, or signal modulators, which result in a SRS-like phenotype. Probands with ring chromosomes or deletions involving the 15q26-qter region present with growth failure and SRS-like features.4–11 It has been proposed that the phenotypes are the result of hemizygosity at the IGF1 receptor ( IGF1R ) gene. We have shown, however, that hemizygosity at this locus is not a common cause of SRS.9,11 In addition, it has been well documented that maternal uniparental disomy (UPD) of chromosome 7 is present in approximately 10% of SRS cases13–16 and no consistent regions of isodisomy have been shown for the full length of the chromosome.17 This suggests that there are imprinted genes on chromosome 7, which when disrupted are responsible for the phenotype. Recently two independently reported candidate gene regions on chromosome 7 containing imprinted genes defined by cytogenetic disruptions in SRS probands have been reported. Two unrelated probands with maternally transmitted duplications of 7p11.2-p13 define the first region.10,18 Recently, a number of other cytogenetic disruptions including balanced translocations and inversions within this region have been described in association with the SRS or SRS-like phenotype19 (Monk et al , manuscript submitted). This candidate gene region contains the growth related genes insulin-like growth factor binding proteins 1 and 3 ( IGFBP s) and growth factor binding protein 10 …