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Disruption of KCNQ1 prevents methylation of the ICR2 and supports the hypothesis that its transcription is necessary for imprint establishment


Beckwith–Wiedemann syndrome (BWS; OMIM #130650) is an imprinting disorder caused by genetic or epigenetic alterations of one or both imprinting control regions on chromosome 11p15.5. Hypomethylation of the centromeric imprinting control region (KCNQ1OT1:TSS-DMR, ICR2) is the most common molecular cause of BWS and is present in about half of the cases. Based on a BWS family with a maternal deletion of the 5’ part of KCNQ1 we have recently hypothesised that transcription of KCNQ1 is a prerequisite for the establishment of methylation at the KCNQ1OT1:TSS-DMR in the oocyte. Further evidence for this hypothesis came from a mouse model where methylation failed to be established when a poly(A) truncation cassette was inserted into this locus to prevent transcription through the DMR. Here we report on a family where a balanced translocation disrupts the KCNQ1 gene in intron 9. Maternal inheritance of this translocation is associated with hypomethylation of the KCNQ1OT1:TSS-DMR and BWS. This finding strongly supports our previous hypothesis that transcription of KCNQ1 is required for establishing the maternal methylation imprint at the KCNQ1OT1:TSS-DMR.

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  1. 1.

    Weksberg R, Shuman C, Beckwith JB. Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2010;18:8–14.

  2. 2.

    Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, et al. Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14:229–49.

  3. 3.

    Choufani S, Shuman C, Weksberg R. Molecular findings in Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet. 2013;163C:131–40.

  4. 4.

    Eggermann T, Algar E, Lapunzina P, Mackay D, Maher ER, Mannens M, et al. Clinical utility gene card for: Beckwith-Wiedemann Syndrome. Eur J Hum Genet. 2014;22.

  5. 5.

    Begemann M, Spengler S, Gogiel M, Grasshoff U, Bonin M, Betz RC, et al. Clinical significance of copy number variations in the 11p15.5 imprinting control regions: new cases and review of the literature. J Med Genet. 2012;49:547–53.

  6. 6.

    Baskin B, Choufani S, Chen YA, Shuman C, Parkinson N, Lemyre E, et al. High frequency of copy number variations (CNVs) in the chromosome 11p15 region in patients with Beckwith-Wiedemann syndrome. Hum Genet. 2014;133:321–30.

  7. 7.

    Gurrieri F, Zollino M, Oliva A, Pascali V, Orteschi D, Pietrobono R, et al. Mild Beckwith-Wiedemann and severe long-QT syndrome due to deletion of the imprinting center 2 on chromosome 11p. Eur J Hum Genet. 2013;21:965–9.

  8. 8.

    Smith AC, Suzuki M, Thompson R, Choufani S, Higgins MJ, Chiu IW, et al. Maternal gametic transmission of translocations or inversions of human chromosome 11p15.5 results in regional DNA hypermethylation and downregulation of CDKN1C expression. Genomics. 2012;99:25–35.

  9. 9.

    Demars J, Rossignol S, Netchine I, Lee KS, Shmela M, Faivre L, et al. New insights into the pathogenesis of Beckwith-Wiedemann and Silver-Russell syndromes: contribution of small copy number variations to 11p15 imprinting defects. Hum Mutat. 2011;32:1171–82.

  10. 10.

    Beygo J, Joksic I, Strom TM, Ludecke HJ, Kolarova J, Siebert R, et al. A maternal deletion upstream of the imprint control region 2 in 11p15 causes loss of methylation and familial Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2016;24:1280–6.

  11. 11.

    Paganini L, Carlessi N, Fontana L, Silipigni R, Motta S, Fiori S, et al. Beckwith-Wiedemann syndrome prenatal diagnosis by methylation analysis in chorionic villi. Epigenetics 2015;10:643–649.

  12. 12.

    Eggermann T, Netchine I, Temple IK, Tumer Z, Monk D, Mackay D, et al. Congenital imprinting disorders: - a network to decipher their aetiology and to improve the diagnostic and clinical care. Clin Epigenetics 2015;7:23.

  13. 13.

    Chotalia M, Smallwood SA, Ruf N, Dawson C, Lucifero D, Frontera M, et al. Transcription is required for establishment of germline methylation marks at imprinted genes. Genes Dev. 2009;23:105–17.

  14. 14.

    Smith EY, Futtner CR, Chamberlain SJ, Johnstone KA, Resnick JL. Transcription is required to establish maternal imprinting at the Prader-Willi syndrome and Angelman syndrome locus. PLoS Genet. 2011;7:e1002422.

  15. 15.

    Lewis MW, Brant JO, Kramer JM, Moss JI, Yang TP, Hansen PJ, et al. Angelman syndrome imprinting center encodes a transcriptional promoter. Proc Natl Acad Sci USA. 2015;112:6871–5.

  16. 16.

    Singh VB, Sribenja S, Wilson KE, Attwood KM, Hillman JC, Pathak S, et al. Blocked transcription through KvDMR1 results in absence of methylation and gene silencing resembling Beckwith-Wiedemann syndrome. Development. 2017;144:1820–30.

  17. 17.

    John RM, Ainscough JF, Barton SC, Surani MA. Distant cis-elements regulate imprinted expression of the mousep57(Kip2) (Cdkn1c) gene: implications for the human disorder, Beckwith--Wiedemann syndrome. Hum Mol Genet. 2001;10:1601–9.

  18. 18.

    Kaltenbach S, Capri Y, Rossignol S, Denjoy I, Soudee S, Aboura A, et al. Beckwith-Wiedemann syndrome and long QT syndrome due to familial-balanced translocation t(11;17)(p15.5; q21.3) involving the KCNQ1 gene. Clin Genet. 2013;84:78–81.

  19. 19.

    Alders M, Bikker H, Christiaans I. Long QT syndrome. In: Adam MP, Ardinger HH, Pagon RA et al., editors. GeneReviews®. Seattle (WA); 1993. updated 2018.

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We thank the family for their participation in this study and Bernhard Horsthemke for helpful discussions and critical reading of the manuscript. This work was funded by the Bundesministerium für Bildung und Forschung (BMBF; Imprinting diseases, grant No. 01GM1513A).

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The authors declare that they have no conflict of interest.

Correspondence to Jasmin Beygo.

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