Epigenotype-phenotype correlations in Silver-Russell syndrome. J Med Genet

North West Thames Regional Genetic Service, Kennedy-Galton Centre, Level 8V, North West London Hospitals NHS Trust, Watford Rd, Harrow, Middlesex HA1 3UJ, UK.
Journal of Medical Genetics (Impact Factor: 6.34). 11/2010; 47(11):760-8. DOI: 10.1136/jmg.2010.079111
Source: PubMed


Silver-Russell syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face and asymmetry. Maternal uniparental disomy (mUPD) of chromosome 7 and hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 are found in 5-10% and up to 60% of patients with SRS, respectively. As many features are non-specific, diagnosis of SRS remains difficult. Studies of patients in whom the molecular diagnosis is confirmed therefore provide valuable clinical information on the condition.
A detailed, prospective study of 64 patients with mUPD7 (n=20) or ICR1 hypomethylation (n=44) was undertaken.
The considerable overlap in clinical phenotype makes it difficult to distinguish these two molecular subgroups reliably. ICR1 hypomethylation was more likely to be scored as 'classical' SRS. Asymmetry, fifth finger clinodactyly and congenital anomalies were more commonly seen with ICR1 hypomethylation, whereas learning difficulties and referral for speech therapy were more likely with mUPD7. Myoclonus-dystonia has been reported previously in one mUPD7 patient. The authors report mild movement disorders in three further cases. No correlation was found between clinical severity and level of ICR1 hypomethylation. Use of assisted reproductive technology in association with ICR1 hypomethylation seems increased compared with the general population. ICR1 hypomethylation was also observed in affected siblings, although recurrence risk remains low in the majority of cases. Overall, a wide range of severity was observed, particularly with ICR1 hypomethylation. A low threshold for investigation of patients with features suggestive, but not typical, of SRS is therefore recommended.

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Available from: Khaled Abu-Amero,
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    • "Silver–Russell syndrome is characterised by intrauterine and/or postnatal growth restriction (≤ −2SD from the mean), relative macrocephaly, typical facial appearances such as triangular-shaped face and frontal bossing, and body asymmetry (Price et al. 1999). Other abnormalities include fifth-finger clinodactyly, café au lait spots, male genital anomalies and speech delay [reviewed in (Wakeling et al. 2010)]. SRS belongs to a group of 'imprinting disorders', which have an estimated incidence of 1 in 7,000 (Abu-Amero et al. 2010). "
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    ABSTRACT: Silver–Russell syndrome (SRS) is a clinically heterogeneous disorder characterised by severe in utero growth restriction and poor postnatal growth, body asymmetry, irregular craniofacial features and several additional minor malformations. The aetiology of SRS is complex and current evidence strongly implicates imprinted genes. Approximately, half of all patients exhibit DNA hypomethylation at the H19/IGF2 imprinted domain, and around 10 % have maternal uniparental disomy of chromosome 7. We measured DNA methylation in 18 SRS patients at >485,000 CpG sites using DNA methylation microarrays. Using a novel bioinformatics methodology specifically designed to identify subsets of patients with a shared epimutation, we analysed methylation changes genome-wide as well as at known imprinted regions to identify SRS-associated epimutations. Our analysis identifies epimutations at the previously characterised domains of H19/IGF2 and at imprinted regions on chromosome 7, providing proof of principle that our methodology can detect DNA methylation changes at imprinted loci. In addition, we discovered two novel epimutations associated with SRS and located at imprinted loci previously linked to relevant mouse and human phenotypes. We identify RB1 as an additional imprinted locus associated with SRS, with a region near the RB1 differentially methylated region hypermethylated in 13/18 (~70 %) patients. We also report 6/18 (~33 %) patients were hypermethylated at a CpG island near the ANKRD11 gene. We do not observe consistent co-occurrence of epimutations at multiple imprinted loci in single SRS individuals. SRS is clinically heterogeneous and the absence of multiple imprinted loci epimutations reflects the heterogeneity at the molecular level. Further stratification of SRS patients by molecular phenotypes might aid the identification of disease causes.
    Human Genetics 01/2015; 134(3). DOI:10.1007/s00439-014-1526-1 · 4.82 Impact Factor
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    • "Additionally, approximately 7% of SRS patients with H19 hypomethylation also have hypomethylated DMRs of other imprinted loci, but the nearby KvDMR shows no signifi cant methylation changes (Penaherrera et al. 2010). These observations of aberrant methylation in SRS correlate to chromosome 7 maternal uniparental disomy, which is seen in 5% of SRS cases (Abu-Amero et al. 2010), has no associated altered methylation at H19 on the maternal chromosome , and results in a similar developmental phenotype as altered methylation (Wakeling et al. 2010). Examination of the histones and chromatin at the IGF2– H19 locus in BWS and SRS show correspondence between DMR status and elements of the imprintome and regulatory system. "
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    ABSTRACT: Imprinted genes form a special subset of the genome, exhibiting monoallelic expression in a parent-of-origin–dependent fashion. This monoallelic expression is controlled by parental-specific epigenetic marks, which are established in gametogenesis and early embryonic development and are persistent in all somatic cells throughout life. We define this specific set of cis-acting epigenetic regulatory elements as the imprintome, a distinct and specially tasked subset of the epigenome. Imprintome elements contain DNA methylation and histone modifications that regulate monoallelic expression by affecting promoter accessibility, chromatin structure, and chromatin configuration. Understanding their regulation is critical because a significant proportion of human imprinted genes are implicated in complex diseases. Significant species variation in the repertoire of imprinted genes and their epigenetic regulation, however, will not allow model organisms solely to be used for this crucial purpose. Ultimately, only the human will suffice to accurately define the human imprintome.
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 12/2012; 53(3-4):341-58. DOI:10.1093/ilar.53.3-4.341 · 2.39 Impact Factor
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    • "Although matUPD and ICR1 hypomethylation patients have overlapping features, asymmetry, fifth finger clinodactyly and congenital anomalies are more commonly seen in patient with ICR1 hypomethylation, whereas learning difficulties and referral for speech therapy are more likely with matUPD7[36]. Our matUPD7 patient had mild dysmorphic features of SRS that was similar to the patients previously described[8, 9, 11]. "
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    ABSTRACT: Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous syndrome which is characterized by severe intrauterine and postnatal growth retardation, and typical characteristic facial dysmorphisms. It has been associated with maternal uniparental disomy (UPD) for chromosome 7 and hypomethylation of imprinting control region 1 (IGF2/H19) in 11p15. UPD refers to the situation in which both copies of a chromosome pair have originated from one parent. UPD can be presented both as partial heterodisomy and isodisomy. The aim of this study was to determine the maternal UPD7 (matUPD7) in 13 Turkish SRS patients. Genotyping for matUPD7 was performed with microsatellite markers by polymerase chain reaction. The maternal UPD7 including the entire chromosome was identified in 1/13 (7.6%) of individuals within SRS patients. There were no significant differences between clinical features of matUPD7 case and other SRS cases except congenital heart defects. It is often difficult to establish diagnosis of a child with intrauterine growth retardation (IUGR), growth failure and dysmorphic features. Thus, screening for matUPD7 in IUGR children with growth failure and mild SRS features might be a valuable diagnostic tool.
    Iranian Journal of Pediatrics 12/2012; 22(4):445-51. · 0.52 Impact Factor
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