11p15 Imprinting Center Region 1 Loss of Methylation Is a Common and Specific Cause of Typical Russell-Silver Syndrome: Clinical Scoring System and Epigenetic-Phenotypic Correlations

Netchine, Irène; Rossignol, Sylvie; Dufourg, Marie‐Noëlle; Azzi, Salah; Rousseau, Alexandra; Périn, Laurence; Houang, Muriel; Steunou, Virginie; Esteva, Blandine; Thibaud, Nathalie; Demay, M; Danton, Fabienne; Petriczko, Elżbieta; Bertrand, Anne-Marie; Heinrichs, Claudine; Carel, Jean‐Claude; Loeuille, G. A.; Pinto, Graziella; Jacquemont, Marie‐Line; Gicquel, Christine; Cabrol, Sylvie; Bouc, Yves Le

doi:10.1210/jc.2007-0354

Cited by 254 publications

(316 citation statements)

References 33 publications

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“…LOM at H19 was the most common methylation anomaly in such patients. Most other studies have concluded that LOM at H19 is very unlikely in those patients without features of RSS; 7,8,15,16 however, in this series two patients with LOM at H19 did not have a diagnosis of RSS clearly suggested on the referral details. They were both from the anonymised recruitment arm and therefore detailed phenotypic information has not been confirmed, but both were referred by clinical geneticists.…”

Section: Discussioncontrasting

confidence: 71%

“…RSS remains a difficult diagnosis to make due to clinical and (epi)genetic heterogeneity. Various clinical criteria have been proposed 6,7 but many of the features are relatively nonspecific, and there is considerable phenotypic overlap between RSS, and low birth weight or short stature due to other causes. Furthermore, some of the features become less apparent with increasing age.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, some of the features become less apparent with increasing age. Molecularly, two well described causes exist: LOM at H19, which is found in 30-60%, [7][8][9] and maternal uniparental disomy of chromosome 7 (mUPD7), which is found in around 5% of well-defined cases. 7 The critical region on chromosome 7 contributing to the RSS phenotype has not yet been established, and there are currently three candidate imprinted regions (MEST/PEG1, GRB10 and PEG10) at which an isolated epigenetic change may conceivably lead to an RSS phenotype.…”

Section: Introductionmentioning

confidence: 99%

“…14 The possibility that LOM at H19, or mUPD7 might not be specific to RSS and might be found in a proportion of patients with isolated pre-and postnatal growth retardation, has also been considered by others. 7,8,15,16 Until recently, the conclusion in each of these studies was that mUPD7 and LOM at H19 were restricted to those with typical RSS features. More recently, less typical patients have been reported.…”

Section: Introductionmentioning

confidence: 99%

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Methylation analysis of 79 patients with growth restriction reveals novel patterns of methylation change at imprinted loci

et al. 2010

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International audienceThis study was an investigation of 79 patients referred to the Wessex Regional Genetics Laboratory with suspected Russell-Silver Syndrome or unexplained short stature/intra uterine growth restriction, warranting genetic investigation. Methylation status was analysed at target sequences within eleven imprinted loci (PLAGL1, IGF2R, PEG10, MEST1, GRB10, KCNQ1OT1, H19, IGF2P0, DLK1, PEG3, NESPAS). 37% (29/79) of samples were demonstrated to have a methylation abnormality. The commonest finding was a loss of methylation at H19 (23/29), as previously reported in Russell-Silver Syndrome. In addition, four of these patients had methylation anomalies at other loci, of whom two show hypomethylation of multiple imprinted loci, and two showed a complete gain of methylation at IGF2R. This latter finding was also present in five further patients who did not have demonstrable changes at H19. In total, 7/79 patients showed a gain of methylation at IGF2R and this was significantly different from a normal control population of 267 individuals (p=0.002). This study demonstrates the importance of widening the epigenetic investigation to include multiple imprinted loci and highlights potential involvement of the IGF2R locus in growth restriction

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Section: Discussioncontrasting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Methylation analysis of 79 patients with growth restriction reveals novel patterns of methylation change at imprinted loci

et al. 2010

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“…46 Epigenetic abnormalities are detected in up to 35-65% of patients, the most frequent one being hypomethylation of the H19 ICR (Table 1). [46][47][48][49][50][51][52] Like BWS cases, a proportion of patients with Silver-Russell syndrome show hypomethylation at multiple ICRs (Table 1). 43,53 Moreover, over two-third of such patients have hypomethylation not only at the maternally methylated ICRs but also at another paternally methylated ICR at the DLK1-MEG3 locus (IG-DMR) ( Table 1).…”

Section: Childhood Diseases Associated With Imprint Establishment or mentioning

confidence: 99%

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Tomizawa

Sasaki

2012

J Hum Genet

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Genomic imprinting is an epigenetic gene-marking phenomenon that occurs in the germline, whereby genes are expressed from only one of the two parental copies in embryos and adults. Imprinting is essential for normal mammalian development and its disruption can cause various developmental defects and diseases. The process of imprinting in the germline involves DNA methylation of the imprint control regions (ICRs), and resulting parental-specific methylation imprints are maintained in the zygote and act as the marks controlling imprinted gene expression. Recent studies in mice have revealed new factors involved in imprint establishment during gametogenesis and maintenance during early development. Clinical studies have identified cases of imprinting disorders where involvement of factors shared by multiple ICRs for establishment or maintenance is suspected. These include Beckwith-Wiedemann syndrome, transient neonatal diabetes, Silver-Russell syndrome and others. More severe disruptions can lead to recurrent molar pregnancy, miscarriage or infertility. Imprinting defects may also occur during assisted reproductive technology or cell reprogramming. In this review, we summarize our current knowledge on the mechanisms of imprint establishment and maintenance, and discuss the relationship with various human disorders.

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Genetics of Silver–Russell Syndrome

Eggermann

2012

Encyclopedia of Life Sciences

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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.

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11p15 Imprinting Center Region 1 Loss of Methylation Is a Common and Specific Cause of Typical Russell-Silver Syndrome: Clinical Scoring System and Epigenetic-Phenotypic Correlations

Abstract: The 11p15 ICR1 epimutation is a major, specific cause of RSS exhibiting failure to thrive. We propose a clinical scoring system (including a BMI < -2 SDS), highly predictive of 11p15 ICR1 LOM, for the diagnosis of RSS.

Cited by 254 publications

References 33 publications

Methylation analysis of 79 patients with growth restriction reveals novel patterns of methylation change at imprinted loci

Methylation analysis of 79 patients with growth restriction reveals novel patterns of methylation change at imprinted loci

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Genetics of Silver–Russell Syndrome

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