Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples

Molecular screening for pathogenic mutations in sudden cardiac death (SCD)-related genes is common practice for SCD cases. However, test results may lead to uncertainty because of the identification of variants of unknown significance (VUS) occurring in up to 70% of total identified variants due to...

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Autores: Coll Vidal, Mònica, Fernández-Falgueras, Anna, Iglesias, Anna, Olmo, Bernat del, Nogué-Navarro, Laia, Simon, Adrià, Perez-Serra, Alexandra, Puigmulé, Marta, López López, Laura, Picó, Ferran, Corona, Mònica, Vallverdú-Prats, Marta, Tirón de Llano, Coloma, Campuzano Larrea, Oscar, Castellà, Josep, Brugada, Ramon, Alcalde Masegu, Mireia
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10256/21943
Acceso en línea:http://hdl.handle.net/10256/21943
Access Level:acceso abierto
Palabra clave:Mort sobtada
Sudden death
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spelling Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death SamplesColl Vidal, MònicaFernández-Falgueras, AnnaIglesias, AnnaOlmo, Bernat delNogué-Navarro, LaiaSimon, AdriàPerez-Serra, AlexandraPuigmulé, MartaLópez López, LauraPicó, FerranCorona, MònicaVallverdú-Prats, MartaTirón de Llano, ColomaCampuzano Larrea, OscarCastellà, JosepBrugada, RamonAlcalde Masegu, MireiaMort sobtadaSudden deathMolecular screening for pathogenic mutations in sudden cardiac death (SCD)-related genes is common practice for SCD cases. However, test results may lead to uncertainty because of the identification of variants of unknown significance (VUS) occurring in up to 70% of total identified variants due to a lack of experimental studies. Genetic variants affecting potential splice site variants are among the most difficult to interpret. The aim of this study was to examine rare intronic variants identified in the exonic flanking sequence to meet two main objectives: first, to validate that canonical intronic variants produce aberrant splicing; second, to determine whether rare intronic variants predicted as VUS may affect the splicing product. To achieve these objectives, 28 heart samples of cases of SCD carrying rare intronic variants were studied. Samples were analyzed using 85 SCD genes in custom panel sequencing. Our results showed that rare intronic variants affecting the most canonical splice sites displayed in 100% of cases that they would affect the splicing product, possibly causing aberrant isoforms. However, 25% of these cases (1/4) showed normal splicing, contradicting the in silico results. On the contrary, in silico results predicted an effect in 0% of cases, and experimental results showed >20% (3/14) unpredicted aberrant splicing. Thus, deep intron variants are likely predicted to not have an effect, which, based on our results, might be an underestimation of their effect and, therefore, of their pathogenicity classification and family members’ follow-upMDPI (Multidisciplinary Digital Publishing Institute)2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionpeer-reviewedapplication/pdfhttp://hdl.handle.net/10256/21943http://hdl.handle.net/10256/21943International Journal of Molecular Sciences, 2022, vol. 23, núm. 20, p. 12640Articles publicats (D-CM)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/semantics/altIdentifier/doi/10.3390/ijms232012640info:eu-repo/semantics/altIdentifier/issn/1661-6596info:eu-repo/semantics/altIdentifier/eissn/1422-0067Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10256/219432026-05-29T05:05:01Z
dc.title.none.fl_str_mv Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples
title Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples
spellingShingle Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples
Coll Vidal, Mònica
Mort sobtada
Sudden death
title_short Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples
title_full Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples
title_fullStr Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples
title_full_unstemmed Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples
title_sort Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples
dc.creator.none.fl_str_mv Coll Vidal, Mònica
Fernández-Falgueras, Anna
Iglesias, Anna
Olmo, Bernat del
Nogué-Navarro, Laia
Simon, Adrià
Perez-Serra, Alexandra
Puigmulé, Marta
López López, Laura
Picó, Ferran
Corona, Mònica
Vallverdú-Prats, Marta
Tirón de Llano, Coloma
Campuzano Larrea, Oscar
Castellà, Josep
Brugada, Ramon
Alcalde Masegu, Mireia
author Coll Vidal, Mònica
author_facet Coll Vidal, Mònica
Fernández-Falgueras, Anna
Iglesias, Anna
Olmo, Bernat del
Nogué-Navarro, Laia
Simon, Adrià
Perez-Serra, Alexandra
Puigmulé, Marta
López López, Laura
Picó, Ferran
Corona, Mònica
Vallverdú-Prats, Marta
Tirón de Llano, Coloma
Campuzano Larrea, Oscar
Castellà, Josep
Brugada, Ramon
Alcalde Masegu, Mireia
author_role author
author2 Fernández-Falgueras, Anna
Iglesias, Anna
Olmo, Bernat del
Nogué-Navarro, Laia
Simon, Adrià
Perez-Serra, Alexandra
Puigmulé, Marta
López López, Laura
Picó, Ferran
Corona, Mònica
Vallverdú-Prats, Marta
Tirón de Llano, Coloma
Campuzano Larrea, Oscar
Castellà, Josep
Brugada, Ramon
Alcalde Masegu, Mireia
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Mort sobtada
Sudden death
topic Mort sobtada
Sudden death
description Molecular screening for pathogenic mutations in sudden cardiac death (SCD)-related genes is common practice for SCD cases. However, test results may lead to uncertainty because of the identification of variants of unknown significance (VUS) occurring in up to 70% of total identified variants due to a lack of experimental studies. Genetic variants affecting potential splice site variants are among the most difficult to interpret. The aim of this study was to examine rare intronic variants identified in the exonic flanking sequence to meet two main objectives: first, to validate that canonical intronic variants produce aberrant splicing; second, to determine whether rare intronic variants predicted as VUS may affect the splicing product. To achieve these objectives, 28 heart samples of cases of SCD carrying rare intronic variants were studied. Samples were analyzed using 85 SCD genes in custom panel sequencing. Our results showed that rare intronic variants affecting the most canonical splice sites displayed in 100% of cases that they would affect the splicing product, possibly causing aberrant isoforms. However, 25% of these cases (1/4) showed normal splicing, contradicting the in silico results. On the contrary, in silico results predicted an effect in 0% of cases, and experimental results showed >20% (3/14) unpredicted aberrant splicing. Thus, deep intron variants are likely predicted to not have an effect, which, based on our results, might be an underestimation of their effect and, therefore, of their pathogenicity classification and family members’ follow-up
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
peer-reviewed
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10256/21943
http://hdl.handle.net/10256/21943
url http://hdl.handle.net/10256/21943
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms232012640
info:eu-repo/semantics/altIdentifier/issn/1661-6596
info:eu-repo/semantics/altIdentifier/eissn/1422-0067
dc.rights.none.fl_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI (Multidisciplinary Digital Publishing Institute)
publisher.none.fl_str_mv MDPI (Multidisciplinary Digital Publishing Institute)
dc.source.none.fl_str_mv International Journal of Molecular Sciences, 2022, vol. 23, núm. 20, p. 12640
Articles publicats (D-CM)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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