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 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.
Authors
- Fredy Chipa (ORCID: https://orcid.org/0000-0001-9914-946X)
- José Cruzalegui (ORCID: https://orcid.org/0000-0003-2382-0979)
- Georgia Sarquella‐Brugada (ORCID: https://orcid.org/0000-0002-6857-8904)
- Antonio Oliva (ORCID: https://orcid.org/0000-0001-7112-9096)
- Estefanía Martinez-Barrios (ORCID: https://orcid.org/0000-0002-5856-1906)
- Rocío Toro (ORCID: https://orcid.org/0000-0003-3136-1776)
- Patricia Cerralbo
- Óscar Campuzano (ORCID: https://orcid.org/0000-0001-5298-5276)
- Andrea Greco (ORCID: https://orcid.org/0000-0003-2863-3195)
- Irene Zschaeck
- Miguel Fogaça da Mata (ORCID: https://orcid.org/0000-0003-3412-2252)
- Simone Grassi (ORCID: https://orcid.org/0000-0002-2420-6658)
- Carles Díez‐López (ORCID: https://orcid.org/0000-0002-3734-4777)
- Sergi César (ORCID: https://orcid.org/0000-0002-2798-1756)
- Núria Díez-Escuté
- Elena Arbelo (ORCID: https://orcid.org/0000-0003-0424-6393)
Institutions
- Università Cattolica del Sacro Cuore (IT)
- Hospital Sant Joan de Déu Barcelona (ES)
- Universitat de Girona (ES)
- Bellvitge University Hospital (ES)
- Universidad de Cádiz (ES)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Centro de Investigación en Red en Enfermedades Cardiovasculares (ES)
- Institut d'Investigació Biomèdica de Girona (ES)
- Centro de Investigación Biomédica en Red (ES)
- Hospital de Santa Cruz (PT)
- Centro Hospitalar de Lisboa Ocidental (PT)
- Sant Joan de Déu Research Foundation (ES)
- ERN GUARD-Heart (NL)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Institut de Recerca Sant Joan de Déu
- University of Florence (IT)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Biomedicines
- Published
- 2024-11-08
- DOI
- https://doi.org/10.3390/biomedicines12112553
- Citations
- 3
- Primary Topic
- Cardiovascular Effects of Exercise
- Type
- article
- Field-Weighted Citation Impact
- 1.21
Funders
- Instituto de Salud Carlos III