Epigenotype–phenotype correlations in Silver–Russell syndrome

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: 5.64). 11/2010; 47(11):760-8. DOI: 10.1136/jmg.2010.079111
Source: PubMed

ABSTRACT 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, Jul 28, 2015
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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 · 4.52 Impact Factor
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    • "en Patienten mit ICR1 - Hypomethylierung zeigen einen typischen SRS - Phänotyp mit intrauteriner und postnataler Wachstumsrestriktion , den charakteristischen kraniofazialen Merkmalen sowie häufig Asymmetrien ( Bliek et al . , 2006 ; Netchine et al . , 2007 ; Binder et al . , 2008 ; Kotzot , 2008 ; Bartholdi et al . , 2009 ; Bruce et al . , 2009 ; Wakeling et al . , 2010"
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