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 |
|---|---|
| Journal | Genetics in Medicine |
| DOIs | |
| Publication status | Accepted/In press - Jan 1 2019 |
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Keywords
- Beckwith–Wiedemann syndrome
- DNA methylation
- genomic imprinting
- imprinting disorders
- long QT syndrome
ASJC Scopus subject areas
- Genetics(clinical)
Cite this
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 journal › Article
}
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
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.
KW - Beckwith–Wiedemann syndrome
KW - DNA methylation
KW - genomic imprinting
KW - imprinting disorders
KW - long QT syndrome
UR - http://www.scopus.com/inward/record.url?scp=85059914542&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85059914542&partnerID=8YFLogxK
U2 - 10.1038/s41436-018-0416-7
DO - 10.1038/s41436-018-0416-7
M3 - Article
AN - SCOPUS:85059914542
JO - Genetics in Medicine
JF - Genetics in Medicine
SN - 1098-3600
ER -