Epigenetic and genetic diagnosis of Silver–Russell syndrome

  title={Epigenetic and genetic diagnosis of Silver–Russell syndrome},
  author={Thomas Eggermann and Sabrina Spengler and Magdalena Gogiel and Matthias Begemann and Miriam Elbracht},
  journal={Expert Review of Molecular Diagnostics},
  pages={459 - 471}
Silver–Russell syndrome (SRS) is a congenital imprinting disorder characterized by intrauterine and postnatal growth restriction and further characteristic features. SRS is genetically heterogenous: 7–10% of patients carry a maternal uniparental disomy of chromosome 7; >38% show a hypomethylation in imprinting control region 1 in 11p15; and a further class of mutations are copy number variations affecting different chromosomes, but mainly 11p15 and 7. The diagnostic work-up should thus aim to… 
Russell–Silver syndrome
  • T. Eggermann
  • Biology
    American journal of medical genetics. Part C, Seminars in medical genetics
  • 2010
The pathophysiological mechanisms resulting in the RSS phenotype still remain unknown despite the recent progress in deciphering the molecular defects associated with this condition, and methylation/genomic testing for chromosome 11p15, UPD(7)mat analysis and molecular karyotyping is recommended.
Silver–Russell syndrome
  • E. Wakeling
  • Medicine
    Archives of Disease in Childhood
  • 2011
Clinicians should have a low threshold for genetic investigation of patients with features suggestive of SRS, including asymmetry, as features vary widely in severity.
Silver-Russell Syndrome - Part I: Clinical Characteristics and Genetic Background.
Silver-Russell syndrome (SRS) is a rare, clinically and genetically heterogeneous entity, caused by (epi)genetic alternations. It is characterized by prenatal and postnatal growth retardation,
Silver-Russell Syndrome and Beckwith-Wiedemann Syndrome: Opposite Phenotypes with Heterogeneous Molecular Etiology
The clinical diagnostic criteria and scoring systems as well as molecular causes in both SRS and BWS are described in detail.
Genome-wide analysis of differential DNA methylation in Silver-Russell syndrome
This study identified the probe cg25963939, located at the 5′UTR of imprinted gene OSBPL5, as a novel DMR that is associated with SRS, and identifies epimutations at the previously characterized domains of H19/IGF2, providing proof of principle that the methodology can detect the changes in DNA methylation at imprinted loci.
Clinical characteristics and chromosome 11p15 imprinting analysis of Silver-Russell syndrome – a Chinese experience
  • Di Wu, C. Gong, C. Su
  • Medicine
    Journal of pediatric endocrinology & metabolism : JPEM
  • 2014
It is demonstrated that Chinese children with SRS had more growth retardation than bone retardation, severely low levels of BMI, triangular faces, and limb asymmetry.
Silver-Russell syndrome . Part II
Clinical criteria serve for screening patients for further genetic tests, and techniques useful for SRS diagnosis include analysis for maternal uniparental disomy (UPD(7)mat) and molecular karyotypying if submicroscopic imbalances are suspected.
Genomic imbalance in the centromeric 11p15 imprinting center in three families: Further evidence of a role for IC2 as a cause of Russell–Silver syndrome
Three new families with genomic imbalances, involving imprinting center 2 resulting in gain of methylation at this center and a Russell–Silver syndrome phenotype are reported, including two families with a maternally inherited microduplication and the first pediatric patient with a paternally derived microdeletion.
Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum
Various IDs constitute underlying factors for SGA-SS, including SRS, including loss of methylation of the H19/IGF2:intergenic-DMR and uniparental disomy chromosome 7, being major genetic causes of SRS.


The genetic aetiology of Silver–Russell syndrome
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.
Silver-Russell syndrome: genetic basis and molecular genetic testing
A diagnostic algorithm is suggested focused on the 11p15 hypomethylation, UPD(7)mat and cryptic chromosomal imbalances for patients with typical SRS phenotype, but also with milder clinical signs only reminiscent for the disease.
Maternal uniparental disomy 7 in Silver-Russell syndrome.
In a prospective study of 33 patients with sporadic SRS, the parent of origin of chromosome 7 is studied using variable number tandem repeat (VNTR) or microsatellite repeat markers and two patients are identified with maternal uniparental disomy of chromosomes 7 (mUPD7).
Epigenotype–phenotype correlations in Silver–Russell syndrome
A wide range of severity was observed, particularly with ICR1 hypomethylation, and a low threshold for investigation of patients with features suggestive, but not typical, of SRS is recommended.
Epigenetic signatures of Silver–Russell syndrome
Interestingly, the degree of hypomethylation was also found to correlate with the severity of the growth phenotype as well as additional SRS diagnostic features, and patients with mUPD7 were clinically distinguishable displaying a noticeably milder phenotype.
Segmental maternal UPD(7q) in Silver–Russell syndrome
In routine diagnostic screening for UPD(7)mat, two patients with SRS features carrying a segmental UPD restricted to 7q which affects the abovementioned imprinted transcripts (Table 1) are identified.
Submicroscopic genomic alterations in Silver–Russell syndrome and Silver–Russell-like patients
The findings emphasise that SRS is heterogeneous in genetic aetiology beyond the major groups of H19 hypomethylation and maternal UPD7 and that unbiased genome-scale screens may reveal novel genotype–phenotype correlations.
Submicroscopic chromosomal imbalances in idiopathic Silver–Russell syndrome (SRS): the SRS phenotype overlaps with the 12q14 microdeletion syndrome
Molecular karyotyping is indicated in SRS and should be included in the diagnostic algorithm, as it is shown that chromosomal aberrations are relevant in this disease.
Broad Clinical Spectrum in Silver-Russell Syndrome and Consequences for Genetic Testing in Growth Retardation
Genetic testing for the 11p15 epimutation and/or maternal uniparental disomy of chromosome 7 should also be considered in case of “Silver-Russell syndrome-like” phenotypes, for example, mild intrauterine growth restriction and postnatal growth retardation associated with a prominent forehead and triangular face or asymmetry as the only clinical signs.
Deletion of the paternal allele of the imprinted MEST/PEG1 region in a patient with Silver–Russell syndrome features
The first case of a de novo deletion in 7q32 affecting the paternal imprinted MEST/PEG1 gene copy and further (imprinted) genes showing clinical features compatible with SRS is reported on.