Genetic variants within the second intron of the<i>KCNQ1</i>gene affect CTCF binding and confer a risk of Beckwith–Wiedemann syndrome upon maternal transmission

Demars, Julie; Shmela, Mansur E; Khan, Abdul Waheed; Lee, Kai Syin; Azzi, Salah; Déhais, Patrice; Netchine, Irène; Rossignol, Sylvie; Bouc, Yves Le; El‐Osta, Assam; Gicquel, Christine

doi:10.1136/jmedgenet-2014-102368

Cited by 15 publications

(16 citation statements)

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“…Similarly, detection of the rare but observable structural rearrangements or copy number variations causing subtle imbalances of the subtelomeric 11p15.5 region requires the integrated application of multicolor fluorescence in situ hybridization (FISH), high-resolution array comparative genomic hybridization (CGH), or SNP array [ 17 – 20 ]. Cis- and trans-acting factors responsible for complex interactions between the 11p15.5 imprinted genes have been identified in both BWS and SRS [ 7 , 21 , 22 ]; however, they are not included in the current diagnostic flowchart as no precise information is available on the fraction of cases accounted for by these mechanisms. Although this point is being addressed by ongoing research, diagnostic laboratories must combine all the indicated approaches to obtain the highest possible detection rate (>80 %) of (epi)genetic alterations in SRS and BWS.…”

Section: Introductionmentioning

confidence: 99%

A multi-method approach to the molecular diagnosis of overt and borderline 11p15.5 defects underlying Silver–Russell and Beckwith–Wiedemann syndromes

et al. 2016

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BackgroundMultiple (epi)genetic defects affecting the expression of the imprinted genes within the 11p15.5 chromosomal region underlie Silver–Russell (SRS) and Beckwith–Wiedemann (BWS) syndromes. The molecular diagnosis of these opposite growth disorders requires a multi-approach flowchart to disclose known primary and secondary (epi)genetic alterations; however, up to 20 and 30 % of clinically diagnosed BWS and SRS cases remain without molecular diagnosis. The complex structure of the 11p15 region with variable CpG methylation and low-rate mosaicism may account for missed diagnoses. Here, we demonstrate the relevance of complementary techniques for the assessment of different CpGs and the importance of testing multiple tissues to increase the SRS and BWS detection rate.ResultsMolecular testing of 147 and 450 clinically diagnosed SRS and BWS cases provided diagnosis in 34 SRS and 185 BWS patients, with 9 SRS and 21 BWS cases remaining undiagnosed and herein referred to as “borderline.” A flowchart including complementary techniques and, when applicable, the analysis of buccal swabs, allowed confirmation of the molecular diagnosis in all borderline cases. Comparison of methylation levels by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in borderline and control cases defined an interval of H19/IGF2:IG-DMR loss of methylation that was distinct between “easy to diagnose” and “borderline” cases, which were characterized by values ≤mean −3 standard deviations (SDs) compared to controls. Values ≥mean +1 SD at H19/IGF2: IG-DMR were assigned to borderline hypermethylated BWS cases and those ≤mean −2 SD at KCNQ1OT1: TSS-DMR to hypomethylated BWS cases; these were supported by quantitative pyrosequencing or Southern blot analysis. Six BWS cases suspected to carry mosaic paternal uniparental disomy of chromosome 11 were confirmed by SNP array, which detected mosaicism till 10 %. Regarding the clinical presentation, borderline SRS were representative of the syndromic phenotype, with exception of one patient, whereas BWS cases showed low frequency of the most common features except hemihyperplasia.ConclusionsA conclusive molecular diagnosis was reached in borderline methylation cases, increasing the detection rate by 6 % for SRS and 5 % for BWS cases. The introduction of complementary techniques and additional tissue analyses into routine diagnostic work-up should facilitate the identification of cases undiagnosed because of mosaicism, a distinctive feature of epigenetic disorders.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0183-8) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

A multi-method approach to the molecular diagnosis of overt and borderline 11p15.5 defects underlying Silver–Russell and Beckwith–Wiedemann syndromes

et al. 2016

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“…Furthermore, a single-nucleotide polymorphism (SNP) in the 5 0 region of the H19 gene and located near CTCF-binding sites has been associated with abnormal birth weight in humans, with a decrease or increase in birth weight, depending on the parental origin of allele [128]; furthermore, SNPs located in critical CTCF and OCT4 binding sites of the H19 ICR region have been associated with increased hypermethylation of specific CpG sites of the maternal H19 allele [129,130] in BWS patients [130], which, in turn, may affect CTCF binding and subsequent IGF 2 expression and growth. Additionally, SNPs in another imprinted gene, KCNQ1, affect CTCF binding to DNA and also correlate with BWS risk [131]. CTCF is also involved, in a methylation-dependent manner, in the modulation of genetic repeat instability, which, in turn, is related to several human disorders resulting from microsatellite expansion [132].…”

Section: Ctcf Fertility and Artsmentioning

confidence: 99%

The Role of CCCTC-Binding Factor (CTCF) in Genomic Imprinting, Development, and Reproduction1

Franco

Prickett

Oakey

2014

Biology of Reproduction

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CCCTC-binding factor (CTCF) is the major protein involved in insulator activity in vertebrates, with widespread DNA binding sites in the genome. CTCF participates in many processes related to global chromatin organization and remodeling, contributing to the repression or activation of gene transcription. It is also involved in epigenetic reprogramming and is essential during gametogenesis and embryo development. Abnormal DNA methylation patterns at CTCF motifs may impair CTCF binding to DNA, and are related to fertility disorders in mammals. Therefore, CTCF and its binding sites are important candidate regions to be investigated as molecular markers for gamete and embryo quality. This article reviews the role of CTCF in genomic imprinting, gametogenesis, and early embryo development and, moreover, highlights potential opportunities for environmental influences associated with assisted reproductive techniques (ARTs) to affect CTCF-mediated processes. We discuss the potential use of CTCF as a molecular marker for assessing gamete and embryo quality in the context of improving the efficiency and safety of ARTs.

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“…[33][34][35] Intronic methylation has been shown to have functional relevance to human disease outcomes; differential methylation of gene variants within the second intron of KCNQ1 affects CTCF binding and confers risk for Beckwith-Wiedemann syndrome, an overgrowth disorder linked to epigenetic defects at imprinted genes. 36 Functional relevance of intronic methylation patterns in mice has been shown, as well. Intronic enhancer activity in the murine sf-1/ad4bp gene is correlated with both DNA methylation pattern and tissue-specific gene expression.…”

Section: Assay Forward Primermentioning

confidence: 99%

Stat3 is a candidate epigenetic biomarker of perinatal Bisphenol A exposure associated with murine hepatic tumors with implications for human health

et al. 2015

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Genetic variants within the second intron of theKCNQ1gene affect CTCF binding and confer a risk of Beckwith–Wiedemann syndrome upon maternal transmission

Abstract: This study shows that genetic variants confer a risk of DNA methylation defect with a parent-of-origin effect and highlights the crucial role of CTCF for the regulation of genomic imprinting of the CDKN1C/KCNQ1 domain.

Cited by 15 publications

References 46 publications

A multi-method approach to the molecular diagnosis of overt and borderline 11p15.5 defects underlying Silver–Russell and Beckwith–Wiedemann syndromes

A multi-method approach to the molecular diagnosis of overt and borderline 11p15.5 defects underlying Silver–Russell and Beckwith–Wiedemann syndromes

The Role of CCCTC-Binding Factor (CTCF) in Genomic Imprinting, Development, and Reproduction1

Stat3 is a candidate epigenetic biomarker of perinatal Bisphenol A exposure associated with murine hepatic tumors with implications for human health

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