Screening of DNA methylation at the H19 promoter or the distal region of its ICR1 ensures efficient detection of chromosome 11p15 epimutations in Russell–Silver syndrome

Horike, Shin‐ichi; Ferreira, José Carlos; Meguro‐Horike, Makiko; Choufani, Sanaa; Smith, Adam C.; Shuman, Cheryl; Meschino, Wendy S.; Chitayat, David; Zackai, Elaine H.; Scherer, Stephen W.; Weksberg, Rosanna

doi:10.1002/ajmg.a.33065

Cited by 41 publications

(28 citation statements)

References 38 publications

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“…[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). 43 This suggests that the primary defect probably affects post-fertilization maintenance.…”

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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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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“…Given this complex genetic etiology, it is not surprising that a number of different chromosomes and potential candidate genes are implicated as the cause of SRS. It is now recognized that UPD(7)mat is causative in about 10% of patients with SRS but the exact gene causing SRS remains unclear, while the frequency of the partial or complete loss of DNA methylation in the differentially methylated region (DMR) of the IGF2/H19 gene on 11p15 in SRS is estimated to be around 35% [Horike et al, 2009;AbuAmero et al, 2010].…”

Section: Introdcutionmentioning

confidence: 99%

Epigenetic profiling of the H19 differentially methylated region and comprehensive whole genome array‐based analysis in Silver–Russell syndrome

Lin

Lee

Hung

et al. 2010

American J of Med Genetics Pt A

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Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous congenital disorder characterized by severe growth retardation. Hypomethylation of the differentially methylated region (DMR) of the H19 gene and uniparental disomy of maternal chromosome 7 is present in ∼45% of the patients with SRS so more than half of these patients have no known genetic etiology. We combined several molecular technologies including multiplex methylation polymerase chain reaction, methylation-sensitive multiple ligation probe-dependent amplification, and methylation-sensitive high-resolution melting to assess the epigenetic status of 34 patients with SRS. Additionally, we applied a whole genome strategy to detect copy number changes and loss of heterozygosity. Thirteen patients (38.2%) had hypomethylation of the DMR of the H19 gene and none had uniparental disomy of maternal chromosome 7. The whole genome arrays identified five patients (14.7%) with microdeletions on chromosomes 1q23q24.3, 7p15.3, 13q31.3, 14q32.31, and 15q26.2qter, respectively. The overall mutation detection rate was 52.9% by the epigenetic study and the whole genome strategy. Although epimutation may be the major cause of SRS and can be identified by multiplex methylation polymerase chain reaction, the whole genome approach also provides information on the etiology of SRS. If no epimutation is identified in the patients with typical SRS, microdeletions should be suspected.

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“…It is recognized that ICR1 is the imprinting center that regulates the telomeric region of the 11p15 region. Furthermore, uneven methylation has been previously reported at the promoter region of H19 [Vu et al, 2000] and dissociation between the methylation status of ICR1 and H19 promoter has been reported in RSS patients [Horike et al, 2009]. Improvements are therefore required in the SALSA ME030B probe set, together with a careful analysis and validation of the results.…”

Section: Discussionmentioning

confidence: 99%

Allele-specific methylated multiplex real-time quantitative PCR (ASMM RTQ-PCR), a powerful method for diagnosing loss of imprinting of the 11p15 region in Russell Silver and Beckwith Wiedemann syndromes

et al. 2011

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Many human syndromes involve a loss of imprinting (LOI) due to a loss (LOM) or a gain of DNA methylation (GOM). Most LOI occur as mosaics and can therefore be difficult to detect with conventional methods. The human imprinted 11p15 region is crucial for the control of fetal growth, and LOI at this locus is associated with two clinical disorders with opposite phenotypes: Beckwith-Wiedemann syndrome (BWS), characterized by fetal overgrowth and a high risk of tumors, and Russell-Silver syndrome (RSS), characterized by intrauterine and postnatal growth restriction. Until recently, we have been using Southern blotting for the diagnosis of RSS and BWS. We describe here a powerful quantitative technique, allele-specific methylated multiplex real-time quantitative PCR (ASMM RTQ-PCR), for the diagnosis of these two complex disorders. We first checked the specificity of the probes and primers used for ASMM RTQ-PCR. We then carried out statistical validation for this method, on both retrospective and prospective populations of patients. This analysis demonstrated that ASMM RTQ-PCR is more sensitive than Southern blotting for detecting low degree of LOI. Moreover, ASMM RTQ-PCR is a very rapid, reliable, simple, safe, and cost effective method.

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Screening of DNA methylation at the H19 promoter or the distal region of its ICR1 ensures efficient detection of chromosome 11p15 epimutations in Russell–Silver syndrome

Cited by 41 publications

References 38 publications

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

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

Epigenetic profiling of the H19 differentially methylated region and comprehensive whole genome array‐based analysis in Silver–Russell syndrome

Allele-specific methylated multiplex real-time quantitative PCR (ASMM RTQ-PCR), a powerful method for diagnosing loss of imprinting of the 11p15 region in Russell Silver and Beckwith Wiedemann syndromes

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