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

doi:10.1038/s41436-018-0416-7

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	1808-1820
Number of pages	13
Journal	Genetics in Medicine
Volume	21
Issue number	8
DOIs	https://doi.org/10.1038/s41436-018-0416-7
Publication status	Published - Aug 2019

Keywords

Beckwith-Wiedemann syndrome
imprinting disorders
genomic imprinting
long QT syndrome
DNA methylation
LONG-QT SYNDROME
COPY NUMBER VARIATIONS
CONTROL REGION
RNA
GENE
PREVALENCE
MECHANISMS
MUTATIONS
DELETION

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Cite this

Valente, F. M., Sparago, A., Freschi, A., Hill-Harfe, K., Maas, S. M., Frints, S. G. M., Alders, M., Pignata, L., Franzese, M., Angelini, C., Carli, D., Mussa, A., Gazzin, A., Gabbarini, F., Acurzio, B., Ferrero, G. B., Bliek, J., Williams, C. A., Riccio, A., & Cerrato, F. (2019). Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith-Wiedemann locus. Genetics in Medicine, 21(8), 1808-1820. https://doi.org/10.1038/s41436-018-0416-7

@article{bf4aaafc6df74e4a80e7bd1e2967fab9,

title = "Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith-Wiedemann locus",

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.",

keywords = "Beckwith-Wiedemann syndrome, imprinting disorders, genomic imprinting, long QT syndrome, DNA methylation, LONG-QT SYNDROME, COPY NUMBER VARIATIONS, CONTROL REGION, RNA, GENE, PREVALENCE, MECHANISMS, MUTATIONS, DELETION",

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

note = "Funding Information: We are very grateful to the patients and their families for their collaboration. This work was supported by Associazione Italiana Ricerca sul Cancro (IG 2016 N.18671 to A.R.), Telethon-Italia (GGP15131 to A.R.), MIUR-CNR Flag Project Epigen (to A.R.), EU-FP7-ITN INGENIUM 290123 (to A.R.), and MIUR-PRIN 2015 JHLY35 (to A.R. and F.C.). Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = aug,

doi = "10.1038/s41436-018-0416-7",

language = "English",

volume = "21",

pages = "1808--1820",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Nature Publishing Group",

number = "8",

}

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, vol. 21, no. 8, pp. 1808-1820. https://doi.org/10.1038/s41436-018-0416-7

TY - JOUR

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

N1 - Funding Information: We are very grateful to the patients and their families for their collaboration. This work was supported by Associazione Italiana Ricerca sul Cancro (IG 2016 N.18671 to A.R.), Telethon-Italia (GGP15131 to A.R.), MIUR-CNR Flag Project Epigen (to A.R.), EU-FP7-ITN INGENIUM 290123 (to A.R.), and MIUR-PRIN 2015 JHLY35 (to A.R. and F.C.). Publisher Copyright: © 2019, The Author(s).

PY - 2019/8

Y1 - 2019/8

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.

KW - Beckwith-Wiedemann syndrome

KW - imprinting disorders

KW - genomic imprinting

KW - long QT syndrome

KW - DNA methylation

KW - LONG-QT SYNDROME

KW - COPY NUMBER VARIATIONS

KW - CONTROL REGION

KW - RNA

KW - GENE

KW - PREVALENCE

KW - MECHANISMS

KW - MUTATIONS

KW - DELETION

U2 - 10.1038/s41436-018-0416-7

DO - 10.1038/s41436-018-0416-7

M3 - Article

C2 - 30635621

SN - 1098-3600

VL - 21

SP - 1808

EP - 1820

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 8

ER -