A maternal deletion upstream of the imprint control region 2 in 11p15 causes loss of methylation and familial Beckwith–Wiedemann syndrome

Beygo, Jasmin; Joksić, Ivana; Strom, Tim M.; Lüdecke, Hermann‐Josef; Kolarova, Julia; Siebert, Reiner; Miković, Željko; Horsthemke, Bernhard; Buiting, Karin

doi:10.1038/ejhg.2016.3

Cited by 20 publications

(17 citation statements)

References 29 publications

(50 reference statements)

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“…49 Furthermore, recent data also suggested that the transcription of KCNQ1 through the KCNQ1OT1-DMR is necessary to establish the methylation imprint. 50 On this background, it seems feasible to hypothesize that the same mechanism applies for the Figure 5 Model for the establishment of the methylation imprint at the MEG8-DMR by transcription transition. Three different situations of the region 14q32 in respect to expression and methylation status at the three DMRs are given.…”

Section: Clinical Findingsmentioning

confidence: 99%

New insights into the imprinted MEG8-DMR in 14q32 and clinical and molecular description of novel patients with Temple syndrome

et al. 2017

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The chromosomal region 14q32 contains several imprinted genes, which are expressed either from the paternal (DLK1 and RTL1) or the maternal (MEG3, RTL1as and MEG8) allele only. Imprinted expression of these genes is regulated by two differentially methylated regions (DMRs), the germline DLK1/MEG3 intergenic (IG)-DMR (MEG3/DLK1:IG-DMR) and the somatic MEG3-DMR (MEG3:TSS-DMR), which are methylated on the paternal and unmethylated on the maternal allele. Disruption of imprinting in the 14q32 region results in two clinically distinct imprinting disorders, Temple syndrome (TS14) and Kagami-Ogata syndrome (KOS14). Another DMR with a yet unknown function is located in intron 2 of MEG8 (MEG8-DMR, MEG8:Int2-DMR). In contrast to the IG-DMR and the MEG3-DMR, this somatic DMR is methylated on the maternal chromosome and unmethylated on the paternal chromosome. We have performed extensive methylation analyses by deep bisulfite sequencing of the IG-DMR, MEG3-DMR and MEG8-DMR in different prenatal tissues including amniotic fluid cells and chorionic villi. In addition, we have studied the methylation pattern of the MEG8-DMR in different postnatal tissues. We show that the MEG8-DMR is hypermethylated in each of 13 non-deletion TS14 patients (seven newly identified and six previously published patients), irrespective of the underlying molecular cause, and is always hypomethylated in the four patients with KOS14, who have different deletions not encompassing the MEG8-DMR itself. The size and the extent of the deletions and the resulting methylation pattern suggest that transcription starting from the MEG3 promoter may be necessary to establish the methylation imprint at the MEG8-DMR.

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Section: Clinical Findingsmentioning

confidence: 99%

New insights into the imprinted MEG8-DMR in 14q32 and clinical and molecular description of novel patients with Temple syndrome

et al. 2017

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“…Some of them include the IC2 domain itself and are therefore associated with a LOM of the IC2. However, there are also cases where a loss of transcription of KCNQ1, either by CNVs or single nucleotide variants (SNVs), causes a LOM of the IC2 [14][15][16]. Remarkably, these genetic alterations affect only KCNQ1 and its regulatory elements, but not the IC2 itself.…”

Section: Introductionmentioning

confidence: 99%

“…It is conceivable that apparently sporadic BWS cases with IC2 LOM are caused by familial pathogenic KCNQ1 variants but remained undetected so far due to the reduced penetrance of LQTS variants. Up to now, six LQTS families have been described in which altered KCNQ1 transcripts lead to BWS in combination with LQTS when inherited from the mother or to isolated LQTS when transmitted from the father [14,[21][22][23]. The different consequences depend on the parental origin of the allele carrying the altered KCNQ1 variant and can therefore be explained by the biallelic expression of KCNQ1 in the heart but monoallelic expression in other tissues [21].…”

Section: Introductionmentioning

confidence: 99%

Frequency of KCNQ1 variants causing loss of methylation of Imprinting Centre 2 in Beckwith-Wiedemann syndrome

et al. 2020

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Background: Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder caused by disturbances of the chromosomal region 11p15.5. The most frequent molecular finding in BWS is loss of methylation (LOM) of the Imprinting Centre 2 (IC2) region on the maternal allele, which is localised in intron 10 of the KCNQ1 gene. In rare cases, LOM of IC2 has been reported in families with KCNQ1 germline variants which additionally cause long-QT syndrome (LQTS). Thus, a functional link between disrupted KCNQ1 transcripts and altered IC2 methylation has been suggested, resulting in the co-occurrence of LQTS and BWS in case of maternal inheritance. Whereas these cases were identified by chance or in patients with abnormal electrocardiograms, a systematic screen for KCNQ1 variants in IC2 LOM carriers has not yet been performed. Results: We analysed 52 BWS patients with IC2 LOM to determine the frequency of germline variants in KCNQ1 by MLPA and an amplicon-based next generation sequencing approach. We identified one patient with a splice site variant causing premature transcription termination of KCNQ1. Conclusions: Our study strengthens the hypothesis that proper KCNQ1 transcription is required for the establishment of IC2 methylation, but that KCNQ1 variants cause IC2 LOM only in a small number of BWS patients.

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“…The transcripts originating here or the process of transcription through the locus is believed to be necessary for the establishment of the maternal methylation imprint [5][6][7]. Similar observations have been made at four other imprinted loci: GNAS/Gnas [8], KCNQ1/Kcnq1 [9][10][11][12], Peg3 [13] and Zrsr1 [14]. Therefore, sequence alterations in the promoter or upstream exons located within the AS-IC might affect transcription in this region and thereby the establishment of the methylation imprint.…”

Section: Introductionmentioning

confidence: 55%

Common genetic variation in the Angelman syndrome imprinting centre affects the imprinting of chromosome 15

et al. 2020

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Angelman syndrome (AS) is a rare neurogenetic imprinting disorder caused by the loss of function of UBE3A. In~3-5% of AS patients, the disease is due to an imprinting defect (ID). These patients lack DNA methylation of the maternal SNRPN promotor so that a large SNRPN sense/UBE3A antisense transcript (SNHG14) is expressed, which silences UBE3A. In very rare cases, the ID is caused by a deletion of the AS imprinting centre (AS-IC). To search for sequence alterations, we sequenced this region in 168 patients without an AS-IC deletion, but did not detect any sequence alteration. However, the AS-IC harbours six common variants (five single nucleotide variants and one TATG insertion/deletion variant), which constitute five common haplotypes. To determine if any of these haplotypes is associated with an increased risk for an ID, we investigated 119 informative AS-ID trios with the transmission disequilibrium test, which is a family-based association test that measures the over-transmission of an allele or haplotype from heterozygous parents to affected offspring. By this we observed maternal over-transmission of haplotype H-AS3 (p = 0.0073). Interestingly, H-AS3 is the only haplotype that includes the TATG deletion allele. We conclude that this haplotype and possibly the TATG deletion, which removes a SOX2 binding site, increases the risk for a maternal ID and AS. Our data strengthen the notion that the AS-IC is important for establishing and/or maintaining DNA methylation at the SNRPN promotor and show that common genetic variation can affect genomic imprinting. 1234567890();,:1234567890();,:

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A maternal deletion upstream of the imprint control region 2 in 11p15 causes loss of methylation and familial Beckwith–Wiedemann syndrome

Cited by 20 publications

References 29 publications

New insights into the imprinted MEG8-DMR in 14q32 and clinical and molecular description of novel patients with Temple syndrome

New insights into the imprinted MEG8-DMR in 14q32 and clinical and molecular description of novel patients with Temple syndrome

Frequency of KCNQ1 variants causing loss of methylation of Imprinting Centre 2 in Beckwith-Wiedemann syndrome

Common genetic variation in the Angelman syndrome imprinting centre affects the imprinting of chromosome 15

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