Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis

Background/Objectives: Inherited arrhythmogenic syndromes comprise a heterogenic group of genetic entities that lead to malignant arrhythmias and sudden cardiac death. Genetic testing has become crucial to understand the disease etiology and allow for the early identification of relatives at risk; h...

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Autores: Martínez Barrios, Estefanía, Greco, Ana Martina, Cruzalegui, José, César Diaz, Sergio, Díez Escuté, Nuria, Cerralbo, Patricia, Chipa, Fredy, Zschaeck, Irene, Fogaça-da-Mata, Miguel, Díez López, Carles, Arbelo, Elena, Grassi, Simone, Oliva, Antonio, Toro, Rocío, Sarquella Brugada, Georgia, Campuzano Larrea, Oscar
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Recursos: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:2445/220033
Acesso em linha:https://hdl.handle.net/2445/220033
Access Level:acceso abierto
Palavra-chave:Malalts cardíacs
Genètica
Malalties del cor
Arrítmia
Cardiac patients
Genetics
Heart diseases
Arrhythmia
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spelling Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic DiagnosisMartínez Barrios, EstefaníaGreco, Ana MartinaCruzalegui, JoséCésar Diaz, SergioDíez Escuté, NuriaCerralbo, PatriciaChipa, FredyZschaeck, IreneFogaça-da-Mata, MiguelDíez López, CarlesArbelo, ElenaGrassi, SimoneOliva, AntonioToro, RocíoSarquella Brugada, GeorgiaCampuzano Larrea, OscarMalalts cardíacsGenèticaMalalties del corArrítmiaCardiac patientsGeneticsHeart diseasesArrhythmiaBackground/Objectives: Inherited arrhythmogenic syndromes comprise a heterogenic group of genetic entities that lead to malignant arrhythmias and sudden cardiac death. Genetic testing has become crucial to understand the disease etiology and allow for the early identification of relatives at risk; however, it requires an accurate interpretation of the data to achieve a clinically actionable outcome. This is particularly challenging for the large number of rare variants obtained by current high-throughput techniques, which are mostly classified as of unknown significance. Methods: In this work, we present a new algorithm for the genetic interpretation of the remaining rare variants in order to shed light on their potential clinical implications and reduce the burden of unknown significance. Results: Our study illustrates the potential utility of our individualized comprehensive stepwise analyses focused on the rare variants associated with IAS, which are currently classified as ambiguous, to further determine their trends towards pathogenicity or benign traits. Conclusions: We advocate for personalized disease-focused population frequency data and family segregation analyses for all rare variants that remain ambiguous to further clarify their role. The current ambiguity should not influence medical decisions, but a potential deleterious role would suggest a closer clinical follow-up and frequent genetic data review for a more personalized clinical approach.MDPI2025202520242025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion12 p.application/pdfhttps://hdl.handle.net/2445/220033Articles publicats en revistes (Medicina)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.3390/biomedicines12112553Biomedicines, 2024, vol. 12, num.11https://doi.org/10.3390/biomedicines12112553cc-by (c) Martínez-Barrios, E. et al., 2024http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2200332026-05-29T05:05:01Z
dc.title.none.fl_str_mv Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis
title Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis
spellingShingle Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis
Martínez Barrios, Estefanía
Malalts cardíacs
Genètica
Malalties del cor
Arrítmia
Cardiac patients
Genetics
Heart diseases
Arrhythmia
title_short Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis
title_full Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis
title_fullStr Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis
title_full_unstemmed Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis
title_sort Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis
dc.creator.none.fl_str_mv Martínez Barrios, Estefanía
Greco, Ana Martina
Cruzalegui, José
César Diaz, Sergio
Díez Escuté, Nuria
Cerralbo, Patricia
Chipa, Fredy
Zschaeck, Irene
Fogaça-da-Mata, Miguel
Díez López, Carles
Arbelo, Elena
Grassi, Simone
Oliva, Antonio
Toro, Rocío
Sarquella Brugada, Georgia
Campuzano Larrea, Oscar
author Martínez Barrios, Estefanía
author_facet Martínez Barrios, Estefanía
Greco, Ana Martina
Cruzalegui, José
César Diaz, Sergio
Díez Escuté, Nuria
Cerralbo, Patricia
Chipa, Fredy
Zschaeck, Irene
Fogaça-da-Mata, Miguel
Díez López, Carles
Arbelo, Elena
Grassi, Simone
Oliva, Antonio
Toro, Rocío
Sarquella Brugada, Georgia
Campuzano Larrea, Oscar
author_role author
author2 Greco, Ana Martina
Cruzalegui, José
César Diaz, Sergio
Díez Escuté, Nuria
Cerralbo, Patricia
Chipa, Fredy
Zschaeck, Irene
Fogaça-da-Mata, Miguel
Díez López, Carles
Arbelo, Elena
Grassi, Simone
Oliva, Antonio
Toro, Rocío
Sarquella Brugada, Georgia
Campuzano Larrea, Oscar
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malalts cardíacs
Genètica
Malalties del cor
Arrítmia
Cardiac patients
Genetics
Heart diseases
Arrhythmia
topic Malalts cardíacs
Genètica
Malalties del cor
Arrítmia
Cardiac patients
Genetics
Heart diseases
Arrhythmia
description Background/Objectives: Inherited arrhythmogenic syndromes comprise a heterogenic group of genetic entities that lead to malignant arrhythmias and sudden cardiac death. Genetic testing has become crucial to understand the disease etiology and allow for the early identification of relatives at risk; however, it requires an accurate interpretation of the data to achieve a clinically actionable outcome. This is particularly challenging for the large number of rare variants obtained by current high-throughput techniques, which are mostly classified as of unknown significance. Methods: In this work, we present a new algorithm for the genetic interpretation of the remaining rare variants in order to shed light on their potential clinical implications and reduce the burden of unknown significance. Results: Our study illustrates the potential utility of our individualized comprehensive stepwise analyses focused on the rare variants associated with IAS, which are currently classified as ambiguous, to further determine their trends towards pathogenicity or benign traits. Conclusions: We advocate for personalized disease-focused population frequency data and family segregation analyses for all rare variants that remain ambiguous to further clarify their role. The current ambiguity should not influence medical decisions, but a potential deleterious role would suggest a closer clinical follow-up and frequent genetic data review for a more personalized clinical approach.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/220033
url https://hdl.handle.net/2445/220033
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/biomedicines12112553
Biomedicines, 2024, vol. 12, num.11
https://doi.org/10.3390/biomedicines12112553
dc.rights.none.fl_str_mv cc-by (c) Martínez-Barrios, E. et al., 2024
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Martínez-Barrios, E. et al., 2024
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 12 p.
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Articles publicats en revistes (Medicina)
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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score 15,811543

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