Role of genetic testing in young patients with idiopathic atrioventricular conduction disease

Angelo Auricchio, Andrea Demarchi, Tardu Özkartal, Daniela Campanale, Maria Luce Caputo, Marcello di Valentino, Andrea Menafoglio, Francois Regoli, Marco Facchini, Alessandro Del Bufalo, Pietro Foglia, Nicola Ferrari, Fulvio Bomio, Argelia Medeiros-Domingo, Tiziano Moccetti, Giovanni B Pedrazzini, Catherine Klersy, Giulio Conte

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AIMS: To investigate the role of genetic testing in patients with idiopathic atrioventricular conduction disease requiring pacemaker (PM) implantation before the age of 50 years.

METHODS AND RESULTS: All consecutive PM implantations in Southern Switzerland between 2010 and 2019 were evaluated. Inclusion criteria were: (i) age at the time of PM implantation: < 50 years; (ii) atrioventricular block (AVB) of unknown aetiology. Study population was investigated by ajmaline challenge and echocardiographic assessment over time. Genetic testing was performed using next-generation sequencing panel, containing 174 genes associated to inherited cardiac diseases, and Sanger sequencing confirmation of suspected variants with clinical implication. Of 2510 patients who underwent PM implantation, 15 (0.6%) were young adults (median age: 44 years, male predominance) presenting with advanced AVB of unknown origin. The average incidence of idiopathic AVB computed over the 2010-2019 time window was 0.7 per 100 000 persons per year (95% CI 0.4-1.2). Most of patients (67%) presented with specific genetic findings (pathogenic variant) or variants of uncertain significance (VUS). A pathogenic variant of PKP2 gene was found in one patient (6.7%) with no overt structural cardiac abnormalities. A VUS of TRPM4, MYBPC3, SCN5A, KCNE1, LMNA, GJA5 genes was found in other nine cases (60%). Of these, three unrelated patients (20%) presented the same heterozygous missense variant c.2531G > A p.(Gly844Asp) in TRPM4 gene. Diagnostic re-assessment over time led to a diagnosis of Brugada syndrome and long-QT syndrome in two patients (13%). No cardiac events occurred during a median follow-up of 72 months.

CONCLUSION: Idiopathic AVB in adults younger than 50 years is a very rare condition with an incidence of 0.7 per 100 000 persons/year. Systematic investigations, including genetic testing and ajmaline challenge, can lead to the achievement of a specific diagnosis in up to 20% of patients. Heterozygous missense variant c.2531G > A p.(Gly844Asp) in TRPM4 gene was found in an additional 20% of unrelated patients, suggesting possible association of the variant with the disease.

Originele taal-2English
Pagina's (van-tot)643-650
Aantal pagina's8
TijdschriftEuropace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology
Nummer van het tijdschrift2
Vroegere onlinedatum10 nov 2022
StatusPublished - 1 feb 2023

Bibliografische nota

Funding Information:
Conflict of interest: A.A. is a consultant to Boston Scientific, Cairdac, Corvia, Microport CRM, EPD Philips, Radcliffe Publisher. He received speaker fees from Boston Scientific, Medtronic, and Microport. He participates in clinical trials sponsored by Boston Scientific, Medtronic, EPD Philips. He has intellectual properties with Boston Scientific, Biosense Webster, and Microport CRM. G.C has received a research grant (PZ00P3_180055) from the Swiss National Science Foundation (SNSF) F.R. has received speaker fees from Medtronic, consulting fees from Daichi Sankyo. C.K. is an occasional statistical consultant to Boston Scientific. All other co-authors do not report conflict of interest.

Funding Information:
This study was supported by a research grant (NO FF21084) from the Swiss Heart Foundation.

Publisher Copyright:
© 2022 The Author(s).

Copyright 2023 Elsevier B.V., All rights reserved.


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