Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith–Wiedemann locus

Federica Maria Valente, Angela Sparago, Andrea Freschi, Katherine Hill-Harfe, Saskia M. Maas, Suzanna Gerarda Maria Frints, Marielle Alders, Laura Pignata, Monica Franzese, Claudia Angelini, Diana Carli, Alessandro Mussa, Andrea Gazzin, Fulvio Gabbarini, Basilia Acurzio, Giovanni Battista Ferrero, Jet Bliek, Charles A. Williams, Andrea Riccio, Flavia Cerrato

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Purpose: Beckwith–Wiedemann syndrome (BWS) is a developmental disorder caused by dysregulation of the imprinted gene cluster of chromosome 11p15.5 and often associated with loss of methylation (LOM) of the imprinting center 2 (IC2) located in KCNQ1 intron 10. To unravel the etiological mechanisms underlying these epimutations, we searched for genetic variants associated with IC2 LOM. Methods: We looked for cases showing the clinical features of both BWS and long QT syndrome (LQTS), which is often associated with KCNQ1 variants. Pathogenic variants were identified by genomic analysis and targeted sequencing. Functional experiments were performed to link these pathogenic variants to the imprinting defect. Results: We found three rare cases in which complete IC2 LOM is associated with maternal transmission of KCNQ1 variants, two of which were demonstrated to affect KCNQ1 transcription upstream of IC2. As a consequence of KCNQ1 haploinsufficiency, these variants also cause LQTS on both maternal and paternal transmission. Conclusion: These results are consistent with the hypothesis that, similar to what has been demonstrated in mouse, lack of transcription across IC2 results in failure of methylation establishment in the female germline and BWS later in development, and also suggest a new link between LQTS and BWS that is important for genetic counseling.

Original languageEnglish
JournalGenetics in Medicine
DOIs
Publication statusAccepted/In press - Jan 1 2019

Fingerprint

Long QT Syndrome
Methylation
Mothers
Haploinsufficiency
Genetic Counseling
Multigene Family
Introns
Chromosomes

Keywords

  • Beckwith–Wiedemann syndrome
  • DNA methylation
  • genomic imprinting
  • imprinting disorders
  • long QT syndrome

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Valente, F. M., Sparago, A., Freschi, A., Hill-Harfe, K., Maas, S. M., Frints, S. G. M., ... Cerrato, F. (Accepted/In press). Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith–Wiedemann locus. Genetics in Medicine. https://doi.org/10.1038/s41436-018-0416-7

Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith–Wiedemann locus. / Valente, Federica Maria; Sparago, Angela; Freschi, Andrea; Hill-Harfe, Katherine; Maas, Saskia M.; Frints, Suzanna Gerarda Maria; Alders, Marielle; Pignata, Laura; Franzese, Monica; Angelini, Claudia; Carli, Diana; Mussa, Alessandro; Gazzin, Andrea; Gabbarini, Fulvio; Acurzio, Basilia; Ferrero, Giovanni Battista; Bliek, Jet; Williams, Charles A.; Riccio, Andrea; Cerrato, Flavia.

In: Genetics in Medicine, 01.01.2019.

Research output: Contribution to journalArticle

Valente, FM, Sparago, A, Freschi, A, Hill-Harfe, K, Maas, SM, Frints, SGM, Alders, M, Pignata, L, Franzese, M, Angelini, C, Carli, D, Mussa, A, Gazzin, A, Gabbarini, F, Acurzio, B, Ferrero, GB, Bliek, J, Williams, CA, Riccio, A & Cerrato, F 2019, 'Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith–Wiedemann locus', Genetics in Medicine. https://doi.org/10.1038/s41436-018-0416-7
Valente, Federica Maria ; Sparago, Angela ; Freschi, Andrea ; Hill-Harfe, Katherine ; Maas, Saskia M. ; Frints, Suzanna Gerarda Maria ; Alders, Marielle ; Pignata, Laura ; Franzese, Monica ; Angelini, Claudia ; Carli, Diana ; Mussa, Alessandro ; Gazzin, Andrea ; Gabbarini, Fulvio ; Acurzio, Basilia ; Ferrero, Giovanni Battista ; Bliek, Jet ; Williams, Charles A. ; Riccio, Andrea ; Cerrato, Flavia. / Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith–Wiedemann locus. In: Genetics in Medicine. 2019.
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abstract = "Purpose: Beckwith–Wiedemann syndrome (BWS) is a developmental disorder caused by dysregulation of the imprinted gene cluster of chromosome 11p15.5 and often associated with loss of methylation (LOM) of the imprinting center 2 (IC2) located in KCNQ1 intron 10. To unravel the etiological mechanisms underlying these epimutations, we searched for genetic variants associated with IC2 LOM. Methods: We looked for cases showing the clinical features of both BWS and long QT syndrome (LQTS), which is often associated with KCNQ1 variants. Pathogenic variants were identified by genomic analysis and targeted sequencing. Functional experiments were performed to link these pathogenic variants to the imprinting defect. Results: We found three rare cases in which complete IC2 LOM is associated with maternal transmission of KCNQ1 variants, two of which were demonstrated to affect KCNQ1 transcription upstream of IC2. As a consequence of KCNQ1 haploinsufficiency, these variants also cause LQTS on both maternal and paternal transmission. Conclusion: These results are consistent with the hypothesis that, similar to what has been demonstrated in mouse, lack of transcription across IC2 results in failure of methylation establishment in the female germline and BWS later in development, and also suggest a new link between LQTS and BWS that is important for genetic counseling.",
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T1 - Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith–Wiedemann locus

AU - Valente, Federica Maria

AU - Sparago, Angela

AU - Freschi, Andrea

AU - Hill-Harfe, Katherine

AU - Maas, Saskia M.

AU - Frints, Suzanna Gerarda Maria

AU - Alders, Marielle

AU - Pignata, Laura

AU - Franzese, Monica

AU - Angelini, Claudia

AU - Carli, Diana

AU - Mussa, Alessandro

AU - Gazzin, Andrea

AU - Gabbarini, Fulvio

AU - Acurzio, Basilia

AU - Ferrero, Giovanni Battista

AU - Bliek, Jet

AU - Williams, Charles A.

AU - Riccio, Andrea

AU - Cerrato, Flavia

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: Beckwith–Wiedemann syndrome (BWS) is a developmental disorder caused by dysregulation of the imprinted gene cluster of chromosome 11p15.5 and often associated with loss of methylation (LOM) of the imprinting center 2 (IC2) located in KCNQ1 intron 10. To unravel the etiological mechanisms underlying these epimutations, we searched for genetic variants associated with IC2 LOM. Methods: We looked for cases showing the clinical features of both BWS and long QT syndrome (LQTS), which is often associated with KCNQ1 variants. Pathogenic variants were identified by genomic analysis and targeted sequencing. Functional experiments were performed to link these pathogenic variants to the imprinting defect. Results: We found three rare cases in which complete IC2 LOM is associated with maternal transmission of KCNQ1 variants, two of which were demonstrated to affect KCNQ1 transcription upstream of IC2. As a consequence of KCNQ1 haploinsufficiency, these variants also cause LQTS on both maternal and paternal transmission. Conclusion: These results are consistent with the hypothesis that, similar to what has been demonstrated in mouse, lack of transcription across IC2 results in failure of methylation establishment in the female germline and BWS later in development, and also suggest a new link between LQTS and BWS that is important for genetic counseling.

AB - Purpose: Beckwith–Wiedemann syndrome (BWS) is a developmental disorder caused by dysregulation of the imprinted gene cluster of chromosome 11p15.5 and often associated with loss of methylation (LOM) of the imprinting center 2 (IC2) located in KCNQ1 intron 10. To unravel the etiological mechanisms underlying these epimutations, we searched for genetic variants associated with IC2 LOM. Methods: We looked for cases showing the clinical features of both BWS and long QT syndrome (LQTS), which is often associated with KCNQ1 variants. Pathogenic variants were identified by genomic analysis and targeted sequencing. Functional experiments were performed to link these pathogenic variants to the imprinting defect. Results: We found three rare cases in which complete IC2 LOM is associated with maternal transmission of KCNQ1 variants, two of which were demonstrated to affect KCNQ1 transcription upstream of IC2. As a consequence of KCNQ1 haploinsufficiency, these variants also cause LQTS on both maternal and paternal transmission. Conclusion: These results are consistent with the hypothesis that, similar to what has been demonstrated in mouse, lack of transcription across IC2 results in failure of methylation establishment in the female germline and BWS later in development, and also suggest a new link between LQTS and BWS that is important for genetic counseling.

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