Genetics of Silver–Russell Syndrome

Abstract

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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References

Abu‐Amero S, Monk D, Frost J et al. (2008) The genetic aetiology of Silver–Russell syndrome. Journal of Medical Genetics 45: 193–199.

Arima T, Kamikihara T, Hayashida T et al. (2005) ZAC, Lit1 (KCNQ1OT1) and p57KIP2 (CKDN1C) are in an imprinted gene network that might play a role in Beckwith–Wiedemann syndrome. Nucleic Acids Research 33: 2650–2660.

Azzi S, Rossignol S, Steunou V et al. (2009) Multilocus analysis in a large cohort of 11p15‐related foetal growth disorders (Russell Silver and Beckwith–Wiedemann syndromes) reveals simultaneous loss of methylation at paternal and maternal imprinted loci. Human Molecular Genetics 18: 4724–4733.

Baple EL, Poole RL, Mansour S et al. (2011) An atypical case of hypomethylation at multiple imprinted loci. European Journal of Human Genetics 19: 360–362.

Bartholdi D, Krajewska‐Walasek M, Ounap K et al. (2009) Epigenetic mutations of the imprinted IGF2‐H19 domain in Silver–Russell syndrome (SRS): results from a large cohort of patients with SRS and SRS‐like phenotypes. Journal of Medical Genetics 46: 192–197.

Begemann M, Spengler S, Kanber D et al. (2011) Silver–Russell patients showing a broad range of ICR1 and ICR2 hypomethylation in different tissues. Clinical Genetics 80: 83–88.

Binder G, Mavridou K, Wollmann HA et al. (2002) Screening for insulin‐like growth factor‐I receptor mutations in patients with Silver–Russell syndrome. Journal of Pediatric Endocrinology and Metabolism 15: 1167–1171.

Binder G, Seidel AK, Weber K et al. (2006) IGFII serum levels are normal in children with Silver–Russell syndrome who frequently carry epimutations at the IGF2 locus. Journal of Clinical Endocrinology and Metabolism 91: 4709–4712.

Bliek J, Alders M, Maas SM et al. (2009a) Lessons from BWS twins: complex maternal and paternal hypomethylation and a common source of haematopoietic stem cells. European Journal of Human Genetics 17: 1625–1634.

Bliek J, Terhal P, van den Bogaard MJ et al. (2006) Hypomethylation of the H19 gene causes not only Silver–Russell syndrome (SRS) but also isolated asymmetry or an SRS‐like phenotype. American Journal of Human Genetics 78: 604–614.

Bliek J, Verde G, Callaway J et al. (2009b) Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith–Wiedemann syndrome. European Journal of Human Genetics 17: 611–619.

Boonen SE, Hahnemann JM, Mackay D et al. (2012) No evidence for pathogenic variants or maternal effect of ZFP57 as the cause of Beckwith–Wiedemann Syndrome. European Journal of Human Genetics. 20: 119–121.

Bruce S, Hannula‐Jouppi K, Puoskari M et al. (2010) Submicroscopic genomic alterations in Silver–Russell syndrome and Silver–Russell‐like patients. Journal of Medical Genetics 47: 816–822.

Choufani S, Shuman C and Weksberg R (2010) Beckwith–Wiedemann syndrome. American Journal of Medical Genetics 154C: 343–354.

Duncan PA, Hall JG, Spario PR et al. (1990) Three generation dominant transmission of the Russell–Silver syndrome. American Journal of Medical Genetics 35: 242–250.

Eggermann T, Eggermann K and Schönherr N (2008b) Growth retardation versus overgrowth: Silver–Russell syndrome is genetically opposite to Beckwith–Wiedemann syndrome. Trends in Genetics 24: 195–204.

Eggermann T, Prager S, Wollmann HA et al. (2007) Hypomethylation in the 11p15 telomeric imprinting domain in a Silver–Russell patient with a CSH1 deletion (17q24) renders a functional role of this alteration unlikely. Journal of Medical Genetics 44: e77.

Eggermann T, Schönherr N, Jäger S et al. (2008a) Segmental maternal UPD(7q) in Silver–Russell syndrome. Clinical Genetics 7: 486–489.

Gicquel C, Rossignol S, Cabrol S et al. (2005) Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver–Russell syndrome. Nature Genetics 37: 1003–1007.

Joyce CA, Sharp A, Walker JM et al. (1999) Duplication of 7p12.1–p13, including GRB10 and IGFBP1, in a mother and daughter with features of Silver–Russell syndrome. Human Genetics 105: 273–280.

Kagami M, Nagai T, Fukami M et al. (2007) Silver–Russell syndrome in a girl born after in vitro fertilization: partial hypermethylation at the differentially methylated region of PEG1/MEST. Journal of Assisted Reproduction and Genetics 24: 131–136.

Khosla S, Dean W, Brown D et al. (2001) Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes. Biology of Reproduction 64: 918–926.

Kotzot D (2008) Maternal uniparental disomy 7 and Silver–Russell syndrome – clinical update and comparison with other subgroups. European Journal of Medical Genetics 51: 444–451.

Kotzot D, Schmitt S, Bernasconi F et al. (1995) Uniparental disomy 7 in Silver–Russell syndrome and primordial growth retardation. Human Molecular Genetics 4: 583–587.

Leach NT, Chudoba I, Stewart TV et al. (2007) Maternally inherited duplication of chromosome 7, dup(7)(p11.2p12), associated with mild cognitive deficit without features of Silver–Russell syndrome. American Journal of Medical Genetics 143: 1489–1493.

Lim D, Bowdin SC, Tee L et al. (2009) Clinical and molecular genetic features of Beckwith–Wiedemann syndrome associated with assisted reproductive technologies. Human Reproduction 24: 741–747.

Mackay DJ, Boonen SE, Clayton‐Smith J et al. (2006) A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus. Human Genetics 120: 262–269.

Mackay DJ, Callaway JL, Marks SM et al. (2008) Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nature Genetics 40: 949–951.

Maher E, Brueton LA, Bowdin SC et al. (2003) Beckwith–Wiedemann syndrome and assisted reproductive technology (ART). Journal of Medical Genetics 40: 62–64.

Monk D, Wakeling EV, Proud D et al. (2000) Duplication of 7p11.2–p13, including GRB10, in Silver–Russell syndrome. American Journal of Human Genetics 66: 36–46.

Nakabayashi K, Bentley L, Hitchins MP et al. (2002) Identification and characterization of an imprinted antisense RNA (MESTIT1) in the human MEST locus on chromosome 7q32. Human Molecular Genetics 11: 1743–1756.

Netchine I, Rossignol S, Dufourg MN et al. (2007) 11p15 ICR1 loss of methylation is a common and specific cause of typical Russell–Silver syndrome: clinical scoring system and epigenetic–phenotypic correlations. Journal of Clinical Endocrinology and Metabolism 92: 3148–3154.

Orstavik KH, Eiklid K, van der Hagen CB et al. (2003) Another case of imprinting defect in a girl with Angelman syndrome who was conceived by intracytoplasmic semen injection. American Journal of Human Genetics 72: 218–219.

Ounap K, Reimand T, Mägli ML et al. (2004) Two sisters with Silver–Russell phenotype. American Journal of Medical Genetics 131A: 301–306.

Paoloni‐Giacobino A and Chaillet JR (2004) Genomic imprinting and assisted reproduction. Reproductive Health 1: 1–7.

Preece MA, Abu‐Amero S, Price M et al. (1997) Maternal uniparental disomy 7 in Silver–Russell syndrome. Journal of Medical Genetics 34: 6–9.

Reik W and Walter J (2001) Genomic imprinting: parental influence on the genome. Nature Reviews Genetics 2: 21–32.

Rossignol S, Steunou V, Chalas C et al. (2006) The epigenetic imprinting defect of patients with Beckwith–Wiedemann syndrome born after assisted reproductive technology is not restricted to the 11p15 region. Journal of Medical Genetics 43: 902–907.

Schieve LA, Meikle SF, Ferre C et al. (2002) Low and very low birth weight in infants conceived with use of assisted reproduction technology. New England Journal of Medicine 346: 731–737.

Schönherr N, Meyer E, Schmidt A et al. (2007) The centromeric 11p15 imprinting center is also involved in Silver–Russell syndrome. Journal of Medical Genetics 44: 59–63.

Spence JE, Perciaccante RG, Greig GM et al. (1988) Uniparental disomy as a mechanism for human genetic disease. American Journal of Human Genetics 42: 217–226.

Spengler S, Gogiel M, Schönherr N et al. (2009) Screening for genomic variants in ZFP57 in Silver–Russell syndrome patients with 11p15 epimutations. European Journal of Medical Genetics 52: 415–416.

Spengler S, Schönherr N, Binder G et al. (2010) Submicroscopic chromosomal imbalances in idiopathic Silver–Russell syndrome (SRS): the SRS phenotype overlaps with the 12q14 microdeletion syndrome. Journal of Medical Genetics 47: 356–360.

Svensson J, Björnstahl A and Ivarsson SA (2005) Increased risk of Silver–Russell syndrome after in vitro fertilisation. Acta Paediatrica 94: 1163–1165.

Turner CL, Mackay DM, Callaway JL et al. (2010) Methylation analysis of 79 patients with growth restriction reveals novel patterns of methylation change at imprinted loci. European Journal of Medical Genetics 17: 648–655.

Wollmann HA (1998) Intrauterine Wachstumsretardierung. Monatsschr Kinderhlkd 146: 714–726.

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.

Buiting K (2010) Prader–Willi syndrome and Angelman syndrome. American Journal of Medical Genetics 154C: 365–376.

Horsthemke B and Ludwig M (2005) Assisted reproduction: the epigenetic perspective. Human Reproduction Update 11: 473–482.

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. http://www.els.net [doi: 10.1002/9780470015902.a0023847]