Genetics of Silver–Russell Syndrome


Human growth is a complex process and requires the appropriate interaction of many factors. Central members in the growth axes are regulated epigenetically and thereby reflect the profound significance of imprinting for correct mammalian ontogenesis. A prominent imprinting disorder associated with a disturbed imprinting is Silver–Russell syndrome (SRS), a congenital disease characterised by intrauterine and post‐natal growth retardation and further characteristic features. SRS is molecularly heterogenous: 7% of patients carry a maternal uniparental disomy of chromosome 7, >38% show a hypomethylation in the imprinting control region 1 in 11p15. Interestingly, hypermethylation of the same region is associated with the overgrowth disease Beckwith–Wiedemann syndrome (BWS), thus SRS and BWS can be regarded as genetically (and clinically) opposite diseases. Because of the different imprinting regions involved, SRS is a suitable model to decipher the role of imprinting in growth and the functional interaction between imprinted genes in different genomic regions.

Key Concepts:

  • Silver–Russell syndrome is a clinically heterogeneous syndrome and belongs to the group of congenital imprinting disorders.

  • Congential imprinting disorders show a broad spectrum of epimutations and mutations in differentially methylated regions.

  • Different chromosomal regions might be affected by molecular alterations in Silver–Russell syndrome, that is chromosomes 7 and 11p15.

  • The functional significance of the observed molecular aberrations in SRS is currently unknown.

  • Multilocus methylation defects are present in a considerable number of patients with imprinting disorders and indicate a general disturbance of the establishment and/or maintenance of imprinting marks.

  • Deciphering the molecular and functional basis for the clinical course of SRS helps to generally understand epigenetic regulation.

Keywords: Silver–Russell syndrome; genomic imprinting; uniparental disomy; multilocus methylation defect; imprinting disorders; chromosomal aberrations; epimutations

Figure 1.

UPD formation by trisomic rescue. Indeed, further mechanisms are known but trisomic rescue is the most frequent one.

Figure 2.

Types of mutations and epimutations of chromosomes 7 and 11, their putative functional relevance detectable in SRS and their frequencies.

Figure 3.

Simplified overview on mutations and epimutations in SRS affecting the imprinting regions in 11p15. Only the major factors regulated by epigenetic mechanisms are shown. Whereas CDKN1C, H19 and KCNQ1 are expressed from the maternal allele, IGF2 and the noncoding RNA KCNQ1OT1 are expressed from the paternal copy. The regulated expression is mediated by CpG methylation and chromatid organisation (not shown).

Figure 4.

Diagnostic workup in SRS (MSA, microsatellite analysis; MLPA, multiplex ligation probe‐dependent amplification; FISH, fluorescence in situ hybridisation).



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Further Reading

Buiting K, Kanber D, Martín‐Subero JI et al. (2008) Clinical features of maternal uniparental disomy 14 in patients with an epimutation and a deletion of the imprinted DLK1/GTL2 gene cluster. Human Mutations 29: 1141–1146.

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Kelsey G (2010) Imprinting on chromosome 20: tissue‐specific imprinting and imprinting mutations in the GNAS locus. American Journal of Medical Genetics 154C: 377–386.

Meyer E, Lim D, Pasha S et al. (2009) Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith–Wiedemann Syndrome). PLoS Genetics 5: e1000423.

Pembrey ME, Bygren LO, Kaati G et al. (2006) Sex‐specific, male‐line transgenerational responses in humans. European Journal of Human Genetics 14: 159–166.

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Eggermann, Thomas(Feb 2012) Genetics of Silver–Russell Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023847]