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Rare Genetic Variants in Young Adults Requiring Pacemaker Implantation

Fecha de publicación: Fecha Ahead of Print:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Ochoa, JP
  • Espinosa, MA
  • Gayan-Ordas, J
  • Fernández-Valledor, A
  • Gallego-Delgado, M
  • Tirón, C
  • Lozano-Ibañez, A
  • García-Pinilla, JM
  • Rodríguez-Palomares, JF
  • Larrañaga-Moreira, JM
  • Llamas-Gómez, H
  • Ripoll-Vera, T
  • Vilches, S
  • Méndez, I
  • Bascompte-Claret, R
  • García-Alvarez, A
  • Villacorta, E
  • Fernandez-Lozano, I
  • Lara-Pezzi, E
  • Garcia-Pavia, P

Grupos

Abstract

BACKGROUND Genetic disease has recently emerged as a cause of cardiac conduction disorders (CCDs), but the diagnostic yield of genetic testing and the contribution of the different genes to CCD is still unsettled. OBJECTIVES This study sought to determine the diagnostic yield of genetic testing in young adults with CCD of unknown etiology requiring pacemaker implantation. We also studied the prevalence of rare protein-altering variants across individual genes and functional gene groups. METHODS We performed whole exome sequencing in 150 patients with CCD of unknown etiology who had permanent pacemaker implanted at age <= 60 years at 14 Spanish hospitals. Prevalence of rare protein-altering variants in patients with CCD was compared with a reference population of 115,522 individuals from gnomAD database (control subjects). RESULTS Among 39 prioritized genes, patients with CCD had more rare protein-altering variants than control subjects (OR: 2.39; 95% CI: 1.75-3.33). Significant enrichment of rare variants in patients with CCD was observed in all functional gene groups except in the desmosomal genes group. Rare variants in the nuclear envelope genes group exhibited the strongest association with CCD (OR: 6.77; 95% CI: 3.71-13.87). Of note, rare variants in sarcomeric genes were also enriched (OR: 1.73; 95% CI: 1.05-3.10). An actionable genetic variant was detected in 21 patients (14%), with LMNA being the most frequently involved gene (4.6%). CONCLUSIONS Unrecognized rare genetic variants increase the risk of CCD in young adults with CCD of unknown etiology. Genetic testing should be performed in patients age <= 60 years with CCD of unknown etiology. The role of genetic variants in sarcomeric genes as a cause of CCD should be further investigated. (JACC Clin Electrophysiol. 2024;10:2250-2260) (c) 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Datos de la publicación

ISSN/ISSNe:
2405-500X, 2405-5018

JACC-Clinical Electrophysiology  ELSEVIER

Tipo:
Article
Páginas:
2250-2260
PubMed:
39001760
Factor de Impacto:
2,115 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 5

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Keywords

  • cardiac conduction disorders; cardiomyopathy; genetics; pacemaker; sudden cardiac death

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