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.

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

Carli D.;Mussa A.;Gazzin A.;Ferrero G. B.;
2019-01-01

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.
2019
21
8
1808
1820
http://www.nature.com/gim/index.html
Beckwith–Wiedemann syndrome; DNA methylation; genomic imprinting; imprinting disorders; long QT syndrome; Adolescent; Adult; Animals; Beckwith-Wiedemann Syndrome; Child; Child, Preschool; Chromosomes, Human, Pair 11; DNA Methylation; Female; Genomic Imprinting; Humans; Infant; Introns; KCNQ1 Potassium Channel; Male; Maternal Inheritance; Mice; Pedigree; Young Adult
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.; Ga...espandi
File in questo prodotto:
File Dimensione Formato  
s41436-018-0416-7.pdf

Accesso aperto

Descrizione: Articolo principale
Tipo di file: PDF EDITORIALE
Dimensione 2.71 MB
Formato Adobe PDF
2.71 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1729390
Citazioni
  • ???jsp.display-item.citation.pmc??? 22
  • Scopus 38
  • ???jsp.display-item.citation.isi??? 30
social impact