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A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions

Achondrogenesis type II (ACG2) is a lethal skeletal dysplasia caused by dominant pathogenic variants in COL2A1. Most of the variants found in patients with ACG2 affect the glycine residue included in the Gly-X-Y tripeptide repeat that characterizes the type II collagen helix. In this study, we repor...

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Autores principales: Bruni, Valentina, Spoleti, Cristina Barbara, La Barbera, Andrea, Dattilo, Vincenzo, Colao, Emma, Votino, Carmela, Bellacchio, Emanuele, Perrotti, Nicola, Giglio, Sabrina, Iuliano, Rodolfo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467821/
https://www.ncbi.nlm.nih.gov/pubmed/34573377
http://dx.doi.org/10.3390/genes12091395
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author Bruni, Valentina
Spoleti, Cristina Barbara
La Barbera, Andrea
Dattilo, Vincenzo
Colao, Emma
Votino, Carmela
Bellacchio, Emanuele
Perrotti, Nicola
Giglio, Sabrina
Iuliano, Rodolfo
author_facet Bruni, Valentina
Spoleti, Cristina Barbara
La Barbera, Andrea
Dattilo, Vincenzo
Colao, Emma
Votino, Carmela
Bellacchio, Emanuele
Perrotti, Nicola
Giglio, Sabrina
Iuliano, Rodolfo
author_sort Bruni, Valentina
collection PubMed
description Achondrogenesis type II (ACG2) is a lethal skeletal dysplasia caused by dominant pathogenic variants in COL2A1. Most of the variants found in patients with ACG2 affect the glycine residue included in the Gly-X-Y tripeptide repeat that characterizes the type II collagen helix. In this study, we reported a case of a novel splicing variant of COL2A1 in a fetus with ACG2. An NGS analysis of fetal DNA revealed a heterozygous variant c.1267-2_1269del located in intron 20/exon 21. The variant occurred de novo since it was not detected in DNA from the blood samples of parents. We generated an appropriate minigene construct to study the effect of the variant detected. The minigene expression resulted in the synthesis of a COL2A1 messenger RNA lacking exon 21, which generated a predicted in-frame deleted protein. Usually, in-frame deletion variants of COL2A1 cause a phenotype such as Kniest dysplasia, which is milder than ACG2. Therefore, we propose that the size and position of an in-frame deletion in COL2A1 may be relevant in determining the phenotype of skeletal dysplasia.
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spelling pubmed-84678212021-09-27 A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions Bruni, Valentina Spoleti, Cristina Barbara La Barbera, Andrea Dattilo, Vincenzo Colao, Emma Votino, Carmela Bellacchio, Emanuele Perrotti, Nicola Giglio, Sabrina Iuliano, Rodolfo Genes (Basel) Article Achondrogenesis type II (ACG2) is a lethal skeletal dysplasia caused by dominant pathogenic variants in COL2A1. Most of the variants found in patients with ACG2 affect the glycine residue included in the Gly-X-Y tripeptide repeat that characterizes the type II collagen helix. In this study, we reported a case of a novel splicing variant of COL2A1 in a fetus with ACG2. An NGS analysis of fetal DNA revealed a heterozygous variant c.1267-2_1269del located in intron 20/exon 21. The variant occurred de novo since it was not detected in DNA from the blood samples of parents. We generated an appropriate minigene construct to study the effect of the variant detected. The minigene expression resulted in the synthesis of a COL2A1 messenger RNA lacking exon 21, which generated a predicted in-frame deleted protein. Usually, in-frame deletion variants of COL2A1 cause a phenotype such as Kniest dysplasia, which is milder than ACG2. Therefore, we propose that the size and position of an in-frame deletion in COL2A1 may be relevant in determining the phenotype of skeletal dysplasia. MDPI 2021-09-10 /pmc/articles/PMC8467821/ /pubmed/34573377 http://dx.doi.org/10.3390/genes12091395 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 Article
Bruni, Valentina
Spoleti, Cristina Barbara
La Barbera, Andrea
Dattilo, Vincenzo
Colao, Emma
Votino, Carmela
Bellacchio, Emanuele
Perrotti, Nicola
Giglio, Sabrina
Iuliano, Rodolfo
A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions
title A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions
title_full A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions
title_fullStr A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions
title_full_unstemmed A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions
title_short A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions
title_sort novel splicing variant of col2a1 in a fetus with achondrogenesis type ii: interpretation of pathogenicity of in-frame deletions
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467821/
https://www.ncbi.nlm.nih.gov/pubmed/34573377
http://dx.doi.org/10.3390/genes12091395
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