Abstract 4361: SCN5A and Lamin A/C Gene Mutations are Highly Prevalent in Patients with Familial Bradyarrhythmic Disorders
Background: Bradyarrhythmic disorders, such as sick sinus syndrome or atrio-ventricular block, require pacemaker implantation in order to relieve symptoms. While the familial forms of these disorders are not rare, the prevalence of genetic mutations thereof, remains unknown.
Methods and Results: 17 unrelated Japanese patients with familial bradyarrhythmic disorders were enrolled. Each family had more than two individuals who received pacemaker implantations. As a result of a comprehensive analysis for candidate genes (SCN5A, HCN4, KCNQ1, KCNH2, KCNE1–3, and lamin A/C), we identified 12 mutations in 17 probands (70.5%); 6 heterozygous SCN5A mutations in 6/17 probands (35.3%) (T187I, W904X, D1275N, K1578fsX52, E1784K, and K1859E), and more surprisingly, 5 lamin A/C mutations in 6/17 patients (35.3%) (E223G, Q258X, S303fsX25, R335W, and A441fsX39). All of the mutant SCN5A, encoding cardiac sodium channels, except for E1784K, demonstrated a loss-of-function type modulation, as evidenced by whole-cell patch-clamp in HEK cells. 3 of 6 SCN5A mutation carriers (T187I, W904X and K1578fsX52) were associated with Brugada syndrome or Brugada ECG. Meanwhile, E1784K, which was reported to exhibit both gain- and loss-of-function type modulations, had an overlap with long QT syndrome. Mutations in lamin A/C, encoding inner nuclear membrane proteins, have been associated with a wide variety of phenotypes including lamin A/C-related cardiomyopathy, a malignant disease manifesting dilated cardiomyopathy (DCM) plus various bradyarrhythmias. 2 out of 6 probands with lamin A/C mutations (S303fsX25 and R335W) showed a typical phenotype; DCM and a family history of ventricular tachycardia (VT) and sudden cardiac death (SCD). However, 4 other probands showed only bradyarrhythmias with normal cardiac function, an atypical form of lamin A/C-related cardiomyopathy, and 2 had a family history of VT or SCD.
Conclusion: SCN5A and lamin A/C gene mutations were highly prevalent in patients with familial bradyarrhythmias. Screening for these gene mutations is highly useful, because the patients might be associated with other underlying diseases, such as other sodium channelopathies or lamin A/C-related cardiomyopathy, which cause life-threatening arrhythmias.