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, 8 (4), 563-80

New Developments in Silver-Russell Syndrome and Implications for Clinical Practice


New Developments in Silver-Russell Syndrome and Implications for Clinical Practice

Miho Ishida. Epigenomics.


Silver-Russell syndrome is a clinically and genetically heterogeneous disorder, characterized by prenatal and postnatal growth restriction, relative macrocephaly, body asymmetry and characteristic facial features. It is one of the imprinting disorders, which results as a consequence of aberrant imprinted gene expressions. Currently, maternal uniparental disomy of chromosome 7 accounts for approximately 10% of Silver-Russell syndrome cases, while ~50% of patients have hypomethylation at imprinting control region 1 at chromosome 11p15.5 locus, leaving ~40% of cases with unknown etiologies. This review aims to provide a comprehensive list of molecular defects in Silver-Russell syndrome reported to date and to highlight the importance of multiple-loci/tissue testing and trio (both parents and proband) screening. The epigenetic and phenotypic overlaps with other imprinting disorders will also be discussed.

Keywords: Silver–Russell syndrome; discordant twins; epigenetics; epigenomic editing; fetal growth; genomic imprinting; multilocus imprinting disturbance.

Conflict of interest statement

Financial & competing interests disclosure M Ishida is funded by Medical Research Council (MRC). The fetal growth and development research group is funded by the MRC, Wellbeing of Women and supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.


<b>Figure 1.</b>
Figure 1.. Summary of reported molecular anomalies of Silver–Russell syndrome.
ICR1: Imprinting control region 1; MLID: Multilocus imprinting disturbance; Upd(7)mat: Maternal uniparental disomy of chromosome 7.
<b>Figure 2.</b>
Figure 2.. Human chromosome 7 ideogram with imprinted genes and chromosomal aberrations reported in Silver–Russell syndrome patients.
Letters (red = maternal expression, blue = paternal expression, purple = biparental imprinting expression and black = biallelic expression). *The imprinting statuses of DDC, DLX5 and COPG2 in humans have conflicting results. SRS: Silver–Russell syndrome; UPD: Uniparental disomy.
<b>Figure 3.</b>
Figure 3.. Schematic representation of the human imprinted cluster at chromosome 11p15.5 implicated in Silver–Russell syndrome and Beckwith–Wiedemann syndrome.
Maternal and paternal chromosomes are represented in pink and blue, respectively. Paternal (blue), maternal (pink) and biallelic (black) and the direction of the transcription are indicated by arrows. Figure orientations: left = centromeric and right = telomeric. The CTCF protein can bind to the unmethylated ICR1, blocking the IGF2 from accessing the downstream enhancers. The methylated ICR1 do not allow CTCF binding, resulting in IGF2 promoter to interact with the enhancers. BWS: Beckwith–Wiedemann syndrome; ICR: Imprinting control region; SRS: Silver–Russell syndrome.
<b>Figure 4.</b>
Figure 4.. Suggested Silver–Russell syndrome diagnostics flow chart.
To test for all known SRS molecular anomalies, combination of different diagnostics techniques should be performed. Blue shade indicates the techniques used in the routine diagnostics (only widely used techniques shown here). Orange shade indicates the techniques that can be used optionally or in the research studies. CGH: Comparative genomic hybridization; ICR1: Imprinting control region 1; MLID: Multilocus imprinting disturbance; NGS: Next-generation sequencing; SRS: Silver–Russell syndrome; Upd(7)mat: Maternal uniparental disomy of chromosome 7.

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