Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis
<b>Background/Objectives:</b> 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 r...
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MDPI AG
2024-11-01
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| author | Estefanía Martínez-Barrios Andrea Greco José Cruzalegui Sergi Cesar Nuria Díez-Escuté Patricia Cerralbo Fredy Chipa Irene Zschaeck Miguel Fogaça-da-Mata Carles Díez-López Elena Arbelo Simone Grassi Antonio Oliva Rocío Toro Georgia Sarquella-Brugada Oscar Campuzano |
| author_facet | Estefanía Martínez-Barrios Andrea Greco José Cruzalegui Sergi Cesar Nuria Díez-Escuté Patricia Cerralbo Fredy Chipa Irene Zschaeck Miguel Fogaça-da-Mata Carles Díez-López Elena Arbelo Simone Grassi Antonio Oliva Rocío Toro Georgia Sarquella-Brugada Oscar Campuzano |
| author_sort | Estefanía Martínez-Barrios |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusions:</b> 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. |
| format | Article |
| id | doaj-art-0a98684aed9d431db97b0bf7ebfde84f |
| institution | OA Journals |
| issn | 2227-9059 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj-art-0a98684aed9d431db97b0bf7ebfde84f2025-08-20T01:53:44ZengMDPI AGBiomedicines2227-90592024-11-011211255310.3390/biomedicines12112553Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic DiagnosisEstefanía Martínez-Barrios0Andrea Greco1José Cruzalegui2Sergi Cesar3Nuria Díez-Escuté4Patricia Cerralbo5Fredy Chipa6Irene Zschaeck7Miguel Fogaça-da-Mata8Carles Díez-López9Elena Arbelo10Simone Grassi11Antonio Oliva12Rocío Toro13Georgia Sarquella-Brugada14Oscar Campuzano15Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainPediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainPediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainPediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainPediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainPediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainPediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainPediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainPediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainCardiovascular Diseases Research Group, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Hospitalet de Llobregat, SpainEuropean Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The NetherlandsDepartment of Health Sciences, Section of Forensic Medical Sciences, University of Florence, Largo Brambilla 3, 50134 Florence, ItalyDepartment of Health Surveillance and Bioethics, Section of Legal Medicine, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, ItalyMedicine Department, School of Medicine, University of Cádiz, 11003 Cádiz, SpainPediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainCentro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain<b>Background/Objectives:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusions:</b> 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.https://www.mdpi.com/2227-9059/12/11/2553sudden cardiac deathinherited arrhythmogenic syndromesgeneticsclinical interpretationvariants of unknown significance |
| spellingShingle | Estefanía Martínez-Barrios Andrea Greco José Cruzalegui Sergi Cesar Nuria Díez-Escuté Patricia Cerralbo Fredy Chipa Irene Zschaeck Miguel Fogaça-da-Mata Carles Díez-López Elena Arbelo Simone Grassi Antonio Oliva Rocío Toro Georgia Sarquella-Brugada Oscar Campuzano Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis Biomedicines sudden cardiac death inherited arrhythmogenic syndromes genetics clinical interpretation variants of unknown significance |
| title | 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_short | 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 |
| topic | sudden cardiac death inherited arrhythmogenic syndromes genetics clinical interpretation variants of unknown significance |
| url | https://www.mdpi.com/2227-9059/12/11/2553 |
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