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Clinical impact of rare variants associated with inherited channelopathies: a 5-year update

A proper interpretation of the pathogenicity of rare variants is crucial before clinical translation. Ongoing addition of new data may modify previous variant classifications; however, how often a reanalysis is necessary remains undefined. We aimed to extensively reanalyze rare variants associated w...

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Autores principales: Sarquella-Brugada, Georgia, Fernandez-Falgueras, Anna, Cesar, Sergi, Arbelo, Elena, Coll, Mónica, Perez-Serra, Alexandra, Puigmulé, Marta, Iglesias, Anna, Alcalde, Mireia, Vallverdú-Prats, Marta, Fiol, Victoria, Ferrer-Costa, Carles, del Olmo, Bernat, Picó, Ferran, Lopez, Laura, García-Alvarez, Ana, Jordà, Paloma, Tiron de Llano, Coloma, Toro, Rocío, Grassi, Simone, Oliva, Antonio, Brugada, Josep, Brugada, Ramon, Campuzano, Oscar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9522753/
https://www.ncbi.nlm.nih.gov/pubmed/34546463
http://dx.doi.org/10.1007/s00439-021-02370-4
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author Sarquella-Brugada, Georgia
Fernandez-Falgueras, Anna
Cesar, Sergi
Arbelo, Elena
Coll, Mónica
Perez-Serra, Alexandra
Puigmulé, Marta
Iglesias, Anna
Alcalde, Mireia
Vallverdú-Prats, Marta
Fiol, Victoria
Ferrer-Costa, Carles
del Olmo, Bernat
Picó, Ferran
Lopez, Laura
García-Alvarez, Ana
Jordà, Paloma
Tiron de Llano, Coloma
Toro, Rocío
Grassi, Simone
Oliva, Antonio
Brugada, Josep
Brugada, Ramon
Campuzano, Oscar
author_facet Sarquella-Brugada, Georgia
Fernandez-Falgueras, Anna
Cesar, Sergi
Arbelo, Elena
Coll, Mónica
Perez-Serra, Alexandra
Puigmulé, Marta
Iglesias, Anna
Alcalde, Mireia
Vallverdú-Prats, Marta
Fiol, Victoria
Ferrer-Costa, Carles
del Olmo, Bernat
Picó, Ferran
Lopez, Laura
García-Alvarez, Ana
Jordà, Paloma
Tiron de Llano, Coloma
Toro, Rocío
Grassi, Simone
Oliva, Antonio
Brugada, Josep
Brugada, Ramon
Campuzano, Oscar
author_sort Sarquella-Brugada, Georgia
collection PubMed
description A proper interpretation of the pathogenicity of rare variants is crucial before clinical translation. Ongoing addition of new data may modify previous variant classifications; however, how often a reanalysis is necessary remains undefined. We aimed to extensively reanalyze rare variants associated with inherited channelopathies originally classified 5 years ago and its clinical impact. In 2016, rare variants identified through genetic analysis were classified following the American College of Medical Genetics and Genomics’ recommendations. Five years later, we have reclassified the same variants following the same recommendations but including new available data. Potential clinical implications were discussed. Our cohort included 49 cases of inherited channelopathies diagnosed in 2016. Update show that 18.36% of the variants changed classification mainly due to improved global frequency data. Reclassifications mostly occurred in minority genes associated with channelopathies. Similar percentage of variants remain as deleterious nowadays, located in main known genes (SCN5A, KCNH2 and KCNQ1). In 2016, 69.38% of variants were classified as unknown significance, but now, 53.06% of variants are classified as such, remaining the most common group. No management was modified after translation of genetic data into clinics. After 5 years, nearly 20% of rare variants associated with inherited channelopathies were reclassified. This supports performing periodic reanalyses of no more than 5 years since last classification. Use of newly available data is necessary, especially concerning global frequencies and family segregation. Personalized clinical translation of rare variants can be crucial to management if a significant change in classification is identified.
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spelling pubmed-95227532022-10-01 Clinical impact of rare variants associated with inherited channelopathies: a 5-year update Sarquella-Brugada, Georgia Fernandez-Falgueras, Anna Cesar, Sergi Arbelo, Elena Coll, Mónica Perez-Serra, Alexandra Puigmulé, Marta Iglesias, Anna Alcalde, Mireia Vallverdú-Prats, Marta Fiol, Victoria Ferrer-Costa, Carles del Olmo, Bernat Picó, Ferran Lopez, Laura García-Alvarez, Ana Jordà, Paloma Tiron de Llano, Coloma Toro, Rocío Grassi, Simone Oliva, Antonio Brugada, Josep Brugada, Ramon Campuzano, Oscar Hum Genet Original Investigation A proper interpretation of the pathogenicity of rare variants is crucial before clinical translation. Ongoing addition of new data may modify previous variant classifications; however, how often a reanalysis is necessary remains undefined. We aimed to extensively reanalyze rare variants associated with inherited channelopathies originally classified 5 years ago and its clinical impact. In 2016, rare variants identified through genetic analysis were classified following the American College of Medical Genetics and Genomics’ recommendations. Five years later, we have reclassified the same variants following the same recommendations but including new available data. Potential clinical implications were discussed. Our cohort included 49 cases of inherited channelopathies diagnosed in 2016. Update show that 18.36% of the variants changed classification mainly due to improved global frequency data. Reclassifications mostly occurred in minority genes associated with channelopathies. Similar percentage of variants remain as deleterious nowadays, located in main known genes (SCN5A, KCNH2 and KCNQ1). In 2016, 69.38% of variants were classified as unknown significance, but now, 53.06% of variants are classified as such, remaining the most common group. No management was modified after translation of genetic data into clinics. After 5 years, nearly 20% of rare variants associated with inherited channelopathies were reclassified. This supports performing periodic reanalyses of no more than 5 years since last classification. Use of newly available data is necessary, especially concerning global frequencies and family segregation. Personalized clinical translation of rare variants can be crucial to management if a significant change in classification is identified. Springer Berlin Heidelberg 2021-09-21 2022 /pmc/articles/PMC9522753/ /pubmed/34546463 http://dx.doi.org/10.1007/s00439-021-02370-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Investigation
Sarquella-Brugada, Georgia
Fernandez-Falgueras, Anna
Cesar, Sergi
Arbelo, Elena
Coll, Mónica
Perez-Serra, Alexandra
Puigmulé, Marta
Iglesias, Anna
Alcalde, Mireia
Vallverdú-Prats, Marta
Fiol, Victoria
Ferrer-Costa, Carles
del Olmo, Bernat
Picó, Ferran
Lopez, Laura
García-Alvarez, Ana
Jordà, Paloma
Tiron de Llano, Coloma
Toro, Rocío
Grassi, Simone
Oliva, Antonio
Brugada, Josep
Brugada, Ramon
Campuzano, Oscar
Clinical impact of rare variants associated with inherited channelopathies: a 5-year update
title Clinical impact of rare variants associated with inherited channelopathies: a 5-year update
title_full Clinical impact of rare variants associated with inherited channelopathies: a 5-year update
title_fullStr Clinical impact of rare variants associated with inherited channelopathies: a 5-year update
title_full_unstemmed Clinical impact of rare variants associated with inherited channelopathies: a 5-year update
title_short Clinical impact of rare variants associated with inherited channelopathies: a 5-year update
title_sort clinical impact of rare variants associated with inherited channelopathies: a 5-year update
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9522753/
https://www.ncbi.nlm.nih.gov/pubmed/34546463
http://dx.doi.org/10.1007/s00439-021-02370-4
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