RT journal article
T1 Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis
A1 Martínez  Barrios, Estefanía
A1 Greco, Andrea
A1 Cruzalegui, José
A1 Cesar, Sergi
A1 Díez Escuté, Nuria
A1 Cerralbo, Patricia
A1 Chipa, Fredy
A1 Zschaeck, Irene
A1 Fogaça-da-Mata, Miguel
A1 Diez López, Carles
A1 Arbelo, Elena
A1 Grassi, Simone
A1 Oliva, Antonio
A1 Toro Cebada, Rocío
A1 Sarquella Brugada, Georgia
A1 Campuzano, Oscar
A2 Medicina
K1 sudden cardiac death
K1 inherited arrhythmogenic syndromes
K1 genetics
K1 clinical interpretation
K1 variants of unknown significance
AB Background/Objectives: Inherited arrhythmogenic syndromes comprise a heterogenicgroup of genetic entities that lead to malignant arrhythmias and sudden cardiac death. Genetic testinghas become crucial to understand the disease etiology and allow for the early identification of relativesat risk; however, it requires an accurate interpretation of the data to achieve a clinically actionableoutcome. This is particularly challenging for the large number of rare variants obtained by currenthigh-throughput techniques, which are mostly classified as of unknown significance. Methods: Inthis work, we present a new algorithm for the genetic interpretation of the remaining rare variantsin order to shed light on their potential clinical implications and reduce the burden of unknownsignificance. Results: Our study illustrates the potential utility of our individualized comprehensivestepwise analyses focused on the rare variants associated with IAS, which are currently classified asambiguous, to further determine their trends towards pathogenicity or benign traits. Conclusions:We advocate for personalized disease-focused population frequency data and family segregationanalyses for all rare variants that remain ambiguous to further clarify their role. The current ambiguityshould not influence medical decisions, but a potential deleterious role would suggest a closer clinicalfollow-up and frequent genetic data review for a more personalized clinical approach.
PB MDPI
SN 2227-9059
YR 2024
FD 2024-11-08
LK http://hdl.handle.net/10498/35838
UL http://hdl.handle.net/10498/35838
LA eng
DS Repositorio Institucional de la Universidad de Cádiz
RD 10-may-2026