Role of genetic testing in young patients with idiopathic atrioventricular conduction disease. Issue 2 (10th November 2022)

• Record Type: Journal Article
• Authors: Auricchio, Angelo; Demarchi, Andrea; Özkartal, Tardu; Campanale, Daniela; Caputo, Maria Luce; di Valentino, Marcello; Menafoglio, Andrea; Regoli, Francois; Facchini, Marco; Del Bufalo, Alessandro; Foglia, Pietro; Ferrari, Nicola; Bomio, Fulvio; Medeiros-Domingo, Argelia; Moccetti, Tiziano; Pedrazzini, Giovanni B; Klersy, Catherine; Conte, Giulio
• Is Part Of: Europace. Volume 25:Issue 2(2023)
• Page Start: 643
• Page End: 650
• Publication Date: 2022-11-10
• Subjects: Pacemaker -- Atrioventricular Block -- Inherited heart disease -- Genetics -- TRPM4; Arrhythmia -- Treatment -- Periodicals; Cardiac pacing -- Periodicals; Catheter ablation -- Periodicals; Heart -- Physiology -- Periodicals; Electrophysiology -- Periodicals; 617.4120645
• DOI: 10.1093/europace/euac196
• Languages: English
• ISSNs: 1099-5129

Abstract

Abstract: 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.