Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation

Grønskov, Karen; Poole, Rebecca L; Hahnemann, Johanne M D; Thomson, Jennifer R.; Tümer, Zeynep; Brøndum‐Nielsen, Karen; Murphy, Rinki; Ravn, Kirstine; Melchior, Linea; Dedic, Alma; Dolmer, Birgitte; Temple, I. Karen; Boonen, Susanne E.; Mackay, Deborah J G

doi:10.1136/jmg.2010.086504

Cited by 36 publications

(37 citation statements)

References 17 publications

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“…However, with our increased knowledge about molecular disturbances in both syndromes, we must adjust risk estimation and counseling. Furthermore, specific mutations have been identified that cause aberrant methylation either by acting in cis (eg, small deletions in ICR1 39 ) or in trans (NLRP2 32 ) In particular, approximately 20% of BWS patients with ICR1 hypermethylation have point mutations or small deletions in OCT4/SOX2-binding sites within the H19-DMR. 26 Thus, to offer genetic counseling to families with IDs, the knowledge of the nature of the mutation or epimutation subtype is essential to delineate exact risk figures, and genetic counseling by an experienced clinical geneticist is emphasized.…”

Section: Recurrence Risk Estimation In Bws and Srsmentioning

confidence: 99%

Prenatal molecular testing for Beckwith–Wiedemann and Silver–Russell syndromes: a challenge for molecular analysis and genetic counseling

et al. 2015

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15Beckwith-Wiedemann and Silver-Russell syndromes (BWS/SRS) are two imprinting disorders (IDs) associated with disturbances of the 11p15.5 chromosomal region. In BWS, epimutations and genomic alterations within 11p15.5 are observed in 470% of patients, whereas in SRS they are observed in about 60% of the cases. In addition, 10% of the SRS patients carry a maternal uniparental disomy of chromosome 7 11p15.5. There is an increasing demand for prenatal testing of these disorders owing to family history, indicative prenatal ultrasound findings or aberrations involving chromosomes 7 and 11. The complex molecular findings underlying these disorders are a challenge not only for laboratories offering these tests but also for geneticists counseling affected families. The scope of counseling must consider the range of detectable disturbances and their origin, the lack of precise quantitative knowledge concerning the inheritance and recurrence risks for the epigenetic abnormalities, which are hallmarks of these developmental disorders. In this paper, experts in the field of BWS and SRS, including members of the European network of congenital IDs (EUCID.net; www.imprinting-disorders.eu), put together their experience and work in the field of 11p15.5-associated IDs with a focus on prenatal testing. Altogether, prenatal tests of 160 fetuses (122 referred for BWS, 38 for SRS testing) from 5 centers were analyzed and reviewed. We summarize the current knowledge on BWS and SRS with respect to diagnostic testing, the consequences for prenatal genetic testing and counseling and our cumulative experience in dealing with these disorders.

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Section: Recurrence Risk Estimation In Bws and Srsmentioning

confidence: 99%

Prenatal molecular testing for Beckwith–Wiedemann and Silver–Russell syndromes: a challenge for molecular analysis and genetic counseling

et al. 2015

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“…Furthermore, the recent identification of a SRS patient with a duplication restricted to the ICR2 suggests that both ICRs on 11p15 are involved in the etiology of the disease [32,33]. However, imbalances affecting only parts of one of the ICRs in 11p15.5 do not reflect this parent-of-origin effect in any case [34,35]; as a result, the interpretation of these unusual findings is difficult, but these cases allow interesting insights in the complex regulation mechanisms within the ICRs in 11p15.5.…”

Section: Chromosome 11p155 Epimutations and Rearrangementsmentioning

confidence: 83%

Epigenetic and genetic diagnosis of Silver–Russell syndrome

Eggermann

Spengler

Gogiel

et al. 2012

Expert Review of Molecular Diagnostics

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Silver-Russell syndrome (SRS) is a congenital imprinting disorder characterized by intrauterine and postnatal growth restriction and further characteristic features. SRS is genetically heterogenous: 7-10% of patients carry a maternal uniparental disomy of chromosome 7; >38% show a hypomethylation in imprinting control region 1 in 11p15; and a further class of mutations are copy number variations affecting different chromosomes, but mainly 11p15 and 7. The diagnostic work-up should thus aim to detect these three molecular subtypes. Numerous techniques are currently applied in genetic SRS testing, but none of them covers all known (epi)mutations, and they should therefore be used synergistically. However, future next-generation sequencing approaches will allow a comprehensive analysis of all types of alterations in SRS.

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“…Nevertheless, in some SRS patients, isolated hypomethylation at the IGF2P0 locus 19,20 has been observed. These patients might be missed by the currently available MS-MLPA analysis, as the IGF2P0 locus is not included.…”

Section: Resultsmentioning

confidence: 99%

Use of multilocus methylation-specific single nucleotide primer extension (MS-SNuPE) technology in diagnostic testing for human imprinted loci

Begemann

Leisten²,

Soellner³

et al. 2012

Epigenetics

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Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation

Cited by 36 publications

References 17 publications

Prenatal molecular testing for Beckwith–Wiedemann and Silver–Russell syndromes: a challenge for molecular analysis and genetic counseling

Prenatal molecular testing for Beckwith–Wiedemann and Silver–Russell syndromes: a challenge for molecular analysis and genetic counseling

Epigenetic and genetic diagnosis of Silver–Russell syndrome

Use of multilocus methylation-specific single nucleotide primer extension (MS-SNuPE) technology in diagnostic testing for human imprinted loci

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