NKX2–5 Pathogenic Variants in Four Families: ASD, Progressive AV Block, and Arrhythmic Risk: A Case Series

All articles of this category (opens in new window) Background: Pathogenic NKX2–5 variants are associated with familial congenital heart disease, most commonly presenting with atrial septal defect (ASD) and progressive atrioventricular (AV) block. While secundum ASD predominates, sinus-venosus defects and additional anomalies have been reported. The management of arrhythmic complications and the identification of individuals requiring device therapy are key aspects of clinical care. Methods: To delineate genotype–phenotype correlations, four families with heterozygous NKX2–5 variants (one nonsense, three frameshift) were retrospectively analyzed to assess penetrance and arrhythmogenic risk. Clinical, genetic, and pedigree data were reviewed, focusing on structural anomalies, conduction disturbances, device implantation, and outcomes. Results: Among eleven confirmed carriers (clinical data available for eight), penetrance for ASD and AV block was high, though incomplete data precluded precise estimates. Seven carriers had ASD (secundum or sinus-venosus type) in combination with progressive AV block. Additionally, one carrier with left ventricular noncompaction, one with impaired systolic function, and two carriers with ventricular arrhythmias (ventricular tachycardia/ventricular fibrillation) were identified. One sudden cardiac death occurred in an untested close relative with previously treated ASD. Device therapy was frequent across all families, with six pacemaker implantations and two subsequent upgrades to implantable cardioverter-defibrillator (ICD). Conclusion: NKX2–5 variants in this series show high penetrance for ASD and AV block but variable expressivity, including sinus-venosus defects, ventricular noncompaction, and systolic dysfunction. The frequent necessity of pacemaker or ICD implantation and the occurrence of sudden cardiac death underscore the arrhythmogenic potential. These findings support family-wide genetic testing, lifelong rhythm surveillance, and early, proactive device therapy strategies. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany