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J Med Genet. Jul 2006; 43(7): 615–616.
Published online Oct 19, 2005. doi:  10.1136/jmg.2005.038687
PMCID: PMC2564559
Epigenetic mutations in 11p15 in Silver‐Russell syndrome are restricted to the telomeric imprinting domain
T Eggermann, N Schönherr, E Meyer, C Obermann, M Mavany, K Eggermann, M B Ranke, and H A Wollmann
T Eggermann, N Schönherr, E Meyer, C Obermann, M Mavany, K Eggermann, Institute of Human Genetics, University Hospital, RWTH Aachen, Aachen, Germany
M B Ranke, H A Wollmann, Children's Hospital, University of Tübingen, Tübingen, Germany
Correspondence to: Dr Thomas Eggermann
Institute of Human Genetics, University Hospital, RWTH Aachen, Pauwelsstr. 30, D‐52074 Aachen, Germany; teggermann@ukaachen.de
Received September 27, 2005; Revised October 17, 2005; Accepted October 18, 2005.
Introduction
Silver‐Russell syndrome (SRS; also know as Russell‐Silver syndrome) is a heterogeneous syndrome which is characterised by severe intrauterine and postnatal growth retardation and typical dysmorphic features. Recently, the first SRS patients with (epi)genetic mutations in 11p15 affecting the telomeric imprinting domain have been identified. Interestingly, opposite mutations are associated with Beckwith‐Wiedemann syndrome (BWS). However, the general significance of epigenetic mutations in 11p15 for the aetiology of SRS remained unclear.
Methods
We screened a cohort of 51 SRS patients for epimutations in ICR1 and KCNQ1OT1 by methylation sensitive Southern blot analyses.
Results
ICR1 demethylation could be observed in 16 of the 51 SRS patients, corresponding to a frequency of approximately 31%. Changes in methylation at the KCNQ1OT1 locus were not detected.
Discussion
Combining these data with those on maternal duplications in 11p15, nearly 35% of SRS cases are associated with detectable (epi)genetic disturbances in 11p15. We now have to also consider a general involvement of 11p15 alterations in growth retarded patients with only minor or without further dysmorphic features. SRS and BWS may now be regarded as two diseases caused by opposite (epi)genetic disturbances of the same chromosomal region displaying opposite clinical pictures.
Keywords: 11p15, Beckwith‐Wiedemann syndrome, epigenetic mutations, Silver‐Russell syndrome
Silver‐Russell syndrome (SRS; also known as Russell‐Silver syndrome) is a heterogeneous syndrome which is mainly characterised by severe intrauterine and postnatal growth retardation (<3rd percentile). The typical craniofacial features include a prominent forehead, a triangular face, hemihypotrophy, and clinodactyly V. So far, little is known about the causes of the disease: several reports on SRS families as well as on chromosomal disturbances point to a genetic background (for a review see Hitchins et al1). In 7–10% of SRS patients, a maternal uniparental disomy of chromosome 7 (UPD7) can be detected.
Recently, six growth retarded patients with duplications of maternal 11p15 were reported; four of these patients showed SRS(‐like) features (for a review see Eggermann et al2). These cases led to the hypothesis that (epi)genetic alterations in 11p15 opposite to those in Beckwith‐Wiedemann syndrome (BWS) are involved in the aetiology of SRS.2 In fact, the first SRS patients with epigenetic mutations in the telomeric imprinting domain of 11p15 have recently been identified: Gicquel et al3 reported an epimutation consisting of a (partial) loss of paternal methylation at the H19‐IGF2 imprinting centre (ICR1), at the H19 promoter, and at the IGF2 DMR2 in five out of nine patients with the classic SRS phenotype. Methylation of KvDMR1 in KCNQ1OT1 was normal in this cohort. However, the general significance of epigenetic mutations for the aetiology of SRS remained unclear due to the small number of patients investigated by Gicquel et al.3
We screened a cohort of 51 SRS patients for epimutations in ICR1 and KCNQ1OT1 using methylation sensitive Southern blot analyses as reported previously.3,4 Total genomic DNA was digested overnight with RsaI and HpaII for ICR1 and with BamHI and NotI for KvDMR1 in KCNQ1OT1. Samples were electrophoresed on 1.2% or 0.7% agarose gels, blotted, and hybridised with digoxigenin labelled PCR products for ICR1 or KCNQ1OT1.3,4 Methylation index was achieved by densitometry of autoradiographs using a GelDoc2000 system (BioRad, Munich, Germany). In these patients, maternal UPD7 and maternal duplications of 11p15 had been previously excluded. All patients showed severe intrauterine and postnatal growth retardation (<3rd percentile) and at least three further signs typical for SRS according to Wollmann et al.5
ICR1 demethylation with an methylation index ranging from 0.20 to 0.37 could be observed in 16 out of 51 SRS patients, corresponding to a frequency of approximately 31%. ICR1 demethylation was excluded in two further patients with maternal UPD7. Changes in methylation at the KCNQ1OT1 locus were not detected in the 51 patients. More than 80% of the patients with ICR1 demethylation showed body asymmetry together with other clinical features, thus supporting a postzygotic origin and mosaicism of the disturbance as suggested by Gicquel et al.3 Assuming this formation mechanism, there may be even more epigenetic alterations, which remain undetected, in the telomeric imprinting region than reported here.
Our data show that ICR1 demethylation is indeed an important, if not the most important, genetic disturbance in SRS. Combining these data with those on maternal duplications in 11p1,2 nearly 35% SRS cases are associated with detectable (epi)genetic disturbances in 11p15 (table 11).). Considering that 7–10% of SRS patients show maternal UPD7 and chromosomal rearrangements affecting 7p11.2–p13, a genetic alteration with probable functional significance can now be diagnosed in more than 45% of SRS cases. As a consequence, the diagnostic algorithm for SRS should comprise conventional cytogenetic analyses, ICR1 methylation analyses, and a search for maternal UPD7.
Table thumbnail
Table 1 Comparison of genetic alterations and their frequencies in BWS and SRS
In contrast to BWS, mutations in the centromeric imprinting domain of 11p15 may be neglected in the aetiology of SRS (table 11).). We found no epimutations of KvDMR1 in any of the 51 patients, nor were mutations in the transcribed sequences of CDKN1C or KCNQ1OT1 detected.6,7 This is in agreement with the results of Gicquel et al3 who excluded changes in methylation of KvDMR1 in their cohort of nine patients.
The surprising data on the significance of 11p15 disturbances in SRS shed more light on the aetiology of the disease, but also raise a lot of questions.
If we assume that the growth retardation is caused by the defective expression of IGF2 as a factor of the IGF/IGF1R axis, several genes in the cascade may be disrupted resulting in similar phenotypes. Indeed, chromosomal aberrations observed in SRS affect the regions 7p11.2–p14 as well as 15q26 which harbour the genes IGFBP1, IGFBP3, GRB10, and IGF1R, but mutations in these genes have previously been excluded in SRS patients (for a review see Hitchins et al1). Since body asymmetry is not restricted to SRS patients with proven 11p15 epimutations, mosaicism for undetected epigenetic alterations or chromosomal aberrations is conceivable and needs further evaluation.
Interestingly, the clinical picture in patients with epigenetic mutations in the telomeric imprinting domain in 11p15 is more consistent with SRS than that in patients with maternal duplications of the same region; among the six duplication carriers reported so far, only four showed SRS features (for a review see Eggermann et al2). Thus many patients with milder symptoms are likely to remain undiagnosed. Consequently, we now have to also consider a general involvement of 11p15 alterations in growth retarded patients with only minor or without further dysmorphic features.
With the identification of a major genetic disruption in SRS, individual and more directed therapy is conceivable. Until recently, it was nearly impossible to define the genetic and functional subgroups of SRS, and thus treatment of the growth retardation was undirected. The response of SRS patients to growth hormone (GH) treatment is highly variable, with approximately half of the patients showing rapid catch‐up growth. The potential for increasing final height using early GH treatment is still being assessed. Interestingly, one of the patients treated successfully is a carrier of a maternal duplication of 11p15.2 It will be interesting to see whether this is a isolated case or whether SRS patients with 11p15 mutations or other 11p15 disturbances in general benefit from GH treatment in comparison with other SRS subgroups.
Similar to Prader‐Willi and Angelman syndrome, SRS and BWS may now be regarded as two diseases caused by opposite (epi)genetic disturbances of the same chromosomal region. Apart from this exciting genetic background, it is in particular interesting that the two imprinting syndromes also display opposite clinical pictures.
Abbreviations
BWS - Beckwith‐Wiedemann syndrome
GH - growth hormone
SRS - Silver‐Russell syndrome
UPD7 - uniparental disomy of chromosome 7
Footnotes
Competing interests: none declared
1. Hitchins M P, Stanier P, Preece M A, Moore G E. Silver‐Russell syndrome: a dissection of the genetic aetiology and candidate chromosomal regions. J Med Genet 2001. 38810–819.819. [PMC free article] [PubMed]
2. Eggermann T, Meyer E, Obermann C, Heil I, Schüler H, Ranke M B, Eggermann K, Wollmann H A. Is maternal duplication of 11p15 associated with Silver‐Russell syndrome? J Med Genet 2005. 42e26. [PMC free article] [PubMed]
3. Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V, Danton F, Thibaud N, Le Merrer M, Burglen L, Betrand A ‐ M, Nechine I, Le Bouc Y. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver Russell syndrome. Nat Genet 2005. 371003–1007.1007. [PubMed]
4. Bliek J, Maas S M, Ruijter J M, Hennekam R C M, Alders M, Westerveld A, Mannens M M A M. Increased tumour risk for BWS patients correlates with aberrant H19 and not KCNQ1OT1 methylation: occurrence of KCNQ1OT1 hypomethylation in familial cases of BWS. Hum Mol Genet 2001. 10467–476.476. [PubMed]
5. Wollmann H A, Kirchner T, Enders H, Preece M A, Ranke M B. Growth and symptoms in Silver‐Russell syndrome: review on the basis of 386 patients. Eur J Pediatr 1995. 154958–968.968. [PubMed]
6. Obermann C, Meyer E, Prager S, Tomiuk J, Wollmann H A, Eggermann T. Searching for genomic variants in IGF2 and CDKN1C in Silver‐Russell syndrome patients. Mol Genet Metab 2004. 82246–250.250. [PubMed]
7. Meyer E, Wollmann H A, Eggermann T. Analysis of genomic variants in the KCNQ1OT1 transcript in Silver‐Russell syndrome patients. Mol Genet Metab 2005. 84376–377.377. [PubMed]
8. Weksberg R, Smith A C, Squire J, Sadowski P. Beckwith‐Wiedemann syndrome demonstrates a role for epigenetic control of normal development. Hum Mol Genet 2003. 12R61–R68.R68. [PubMed]
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