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Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome

BACKGROUND: Pathogenic CDKN1C gain-of-function variants on the maternal allele were initially reported as a cause of IMAGe syndrome characterized by intrauterine growth retardation, metaphyseal dysplasia, primary adrenal insufficiency and genital anomalies. Recently, a maternally inherited CDKN1C mi...

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Autores principales: Binder, Gerhard, Ziegler, Julian, Schweizer, Roland, Habhab, Wisam, Haack, Tobias B., Heinrich, Tilman, Eggermann, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574352/
https://www.ncbi.nlm.nih.gov/pubmed/33076988
http://dx.doi.org/10.1186/s13148-020-00945-y
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author Binder, Gerhard
Ziegler, Julian
Schweizer, Roland
Habhab, Wisam
Haack, Tobias B.
Heinrich, Tilman
Eggermann, Thomas
author_facet Binder, Gerhard
Ziegler, Julian
Schweizer, Roland
Habhab, Wisam
Haack, Tobias B.
Heinrich, Tilman
Eggermann, Thomas
author_sort Binder, Gerhard
collection PubMed
description BACKGROUND: Pathogenic CDKN1C gain-of-function variants on the maternal allele were initially reported as a cause of IMAGe syndrome characterized by intrauterine growth retardation, metaphyseal dysplasia, primary adrenal insufficiency and genital anomalies. Recently, a maternally inherited CDKN1C missense mutation (p.Arg279Leu) was identified in several members of a single family clinically diagnosed with Silver–Russell syndrome (SRS) but without adrenal insufficiency. Thereafter, two half siblings from UK with familial SRS were described who carried the same mutation. This specific amino acid change is located within a narrow functional region containing the mutations previously associated with IMAGe syndrome. RESULTS: Here, we describe a third familial case with maternally inherited SRS due to a missense variant affecting the same amino acid position 279 but leading to a different amino acid substitution (p. (Arg279Ser)). The two affected family members (mother and son) presented with the complete SRS phenotype (both Netchine–Harbison CSS score 5 of 6) but without body asymmetry or adrenal insufficiency. CONCLUSIONS: In comparison with loss-of-function genomic IGF2 mutations, CDKN1C gain-of-function mutations are a less frequent cause of SRS and seem to affect a cluster of few amino acids.
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spelling pubmed-75743522020-10-20 Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome Binder, Gerhard Ziegler, Julian Schweizer, Roland Habhab, Wisam Haack, Tobias B. Heinrich, Tilman Eggermann, Thomas Clin Epigenetics Research BACKGROUND: Pathogenic CDKN1C gain-of-function variants on the maternal allele were initially reported as a cause of IMAGe syndrome characterized by intrauterine growth retardation, metaphyseal dysplasia, primary adrenal insufficiency and genital anomalies. Recently, a maternally inherited CDKN1C missense mutation (p.Arg279Leu) was identified in several members of a single family clinically diagnosed with Silver–Russell syndrome (SRS) but without adrenal insufficiency. Thereafter, two half siblings from UK with familial SRS were described who carried the same mutation. This specific amino acid change is located within a narrow functional region containing the mutations previously associated with IMAGe syndrome. RESULTS: Here, we describe a third familial case with maternally inherited SRS due to a missense variant affecting the same amino acid position 279 but leading to a different amino acid substitution (p. (Arg279Ser)). The two affected family members (mother and son) presented with the complete SRS phenotype (both Netchine–Harbison CSS score 5 of 6) but without body asymmetry or adrenal insufficiency. CONCLUSIONS: In comparison with loss-of-function genomic IGF2 mutations, CDKN1C gain-of-function mutations are a less frequent cause of SRS and seem to affect a cluster of few amino acids. BioMed Central 2020-10-19 /pmc/articles/PMC7574352/ /pubmed/33076988 http://dx.doi.org/10.1186/s13148-020-00945-y Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Binder, Gerhard
Ziegler, Julian
Schweizer, Roland
Habhab, Wisam
Haack, Tobias B.
Heinrich, Tilman
Eggermann, Thomas
Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome
title Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome
title_full Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome
title_fullStr Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome
title_full_unstemmed Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome
title_short Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome
title_sort novel mutation points to a hot spot in cdkn1c causing silver–russell syndrome
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574352/
https://www.ncbi.nlm.nih.gov/pubmed/33076988
http://dx.doi.org/10.1186/s13148-020-00945-y
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