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Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by prenatal and/or postnatal overgrowth, organomegaly, abdominal wall defects and tumor predisposition. CDKN1C is a maternally expressed gene of the 11p15.5 chromosomal region and is regulated by the imprinting control region...

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Autores principales: Sparago, Angela, Cerrato, Flavia, Pignata, Laura, Cammarata-Scalisi, Francisco, Garavelli, Livia, Piscopo, Carmelo, Vancini, Alessandra, Riccio, Andrea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151838/
https://www.ncbi.nlm.nih.gov/pubmed/34065128
http://dx.doi.org/10.3390/genes12050706
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author Sparago, Angela
Cerrato, Flavia
Pignata, Laura
Cammarata-Scalisi, Francisco
Garavelli, Livia
Piscopo, Carmelo
Vancini, Alessandra
Riccio, Andrea
author_facet Sparago, Angela
Cerrato, Flavia
Pignata, Laura
Cammarata-Scalisi, Francisco
Garavelli, Livia
Piscopo, Carmelo
Vancini, Alessandra
Riccio, Andrea
author_sort Sparago, Angela
collection PubMed
description Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by prenatal and/or postnatal overgrowth, organomegaly, abdominal wall defects and tumor predisposition. CDKN1C is a maternally expressed gene of the 11p15.5 chromosomal region and is regulated by the imprinting control region IC2. It negatively controls cellular proliferation, and its expression or activity are frequently reduced in BWS. In particular, loss of IC2 methylation is associated with CDKN1C silencing in the majority of sporadic BWS cases, and maternally inherited loss-of-function variants of CDKN1C are the most frequent molecular defects of familial BWS. We have identified, using Sanger sequencing, novel CDKN1C variants in three families with recurrent cases of BWS, and a previously reported variant in a woman with recurrent miscarriages with exomphalos. Clinical evaluation of the patients showed variable manifestation of the disease. The frameshift and nonsense variants were consistently associated with exomphalos, while the missense variant caused a less severe phenotype. Pregnancy loss and perinatal lethality were found in the families segregating nonsense mutations. Intrafamilial variability of the clinical BWS features was observed, even between siblings. Our data are indicative of severe BWS phenotypes that, with variable expressivity, may be associated with both frameshift and nonsense variants of CDKN1C.
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spelling pubmed-81518382021-05-27 Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C Sparago, Angela Cerrato, Flavia Pignata, Laura Cammarata-Scalisi, Francisco Garavelli, Livia Piscopo, Carmelo Vancini, Alessandra Riccio, Andrea Genes (Basel) Case Report Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by prenatal and/or postnatal overgrowth, organomegaly, abdominal wall defects and tumor predisposition. CDKN1C is a maternally expressed gene of the 11p15.5 chromosomal region and is regulated by the imprinting control region IC2. It negatively controls cellular proliferation, and its expression or activity are frequently reduced in BWS. In particular, loss of IC2 methylation is associated with CDKN1C silencing in the majority of sporadic BWS cases, and maternally inherited loss-of-function variants of CDKN1C are the most frequent molecular defects of familial BWS. We have identified, using Sanger sequencing, novel CDKN1C variants in three families with recurrent cases of BWS, and a previously reported variant in a woman with recurrent miscarriages with exomphalos. Clinical evaluation of the patients showed variable manifestation of the disease. The frameshift and nonsense variants were consistently associated with exomphalos, while the missense variant caused a less severe phenotype. Pregnancy loss and perinatal lethality were found in the families segregating nonsense mutations. Intrafamilial variability of the clinical BWS features was observed, even between siblings. Our data are indicative of severe BWS phenotypes that, with variable expressivity, may be associated with both frameshift and nonsense variants of CDKN1C. MDPI 2021-05-09 /pmc/articles/PMC8151838/ /pubmed/34065128 http://dx.doi.org/10.3390/genes12050706 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Case Report
Sparago, Angela
Cerrato, Flavia
Pignata, Laura
Cammarata-Scalisi, Francisco
Garavelli, Livia
Piscopo, Carmelo
Vancini, Alessandra
Riccio, Andrea
Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C
title Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C
title_full Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C
title_fullStr Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C
title_full_unstemmed Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C
title_short Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C
title_sort variable expressivity of the beckwith-wiedemann syndrome in four pedigrees segregating loss-of-function variants of cdkn1c
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151838/
https://www.ncbi.nlm.nih.gov/pubmed/34065128
http://dx.doi.org/10.3390/genes12050706
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