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Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith–Wiedemann locus
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Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith–Wiedemann locus
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Journal Article
Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith–Wiedemann locus
2019
Overview
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.
Publisher
Nature Publishing Group US,Elsevier Limited
Subject
/ Adult
/ Animals
/ Beckwith-Wiedemann Syndrome - epidemiology
/ Beckwith-Wiedemann Syndrome - genetics
/ Beckwith-Wiedemann Syndrome - pathology
/ Biomedical and Life Sciences
/ Child
/ Chromosomes, Human, Pair 11 - genetics
/ Female
/ Genomic Imprinting - genetics
/ Humans
/ Infant
/ KCNQ1 Potassium Channel - genetics
/ Male
/ Maternal Inheritance - genetics
/ Mice
/ Pedigree
