SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism

Abstract

Objectives: The aim of this study was to discern the role of the cardiac voltage-gated sodium ion channel SCN5A in the etiology of dilated cardiomyopathy (DCM).

Background: Dilated cardiomyopathy associates with mutations in the SCN5A gene, but the frequency, phenotype, and causative nature of these associations remain the focus of ongoing investigation.

Methods: Since 1991, DCM probands and family members have been enrolled in the Familial Cardiomyopathy Registry and extensively evaluated by clinical phenotype. Genomic deoxyribonucleic acid samples from 338 individuals among 289 DCM families were obtained and screened for SCN5A mutations by denaturing high-performance liquid chromatography and sequence analysis.

Results: We identified 5 missense SCN5A mutations among our DCM families, including novel mutations E446K, F1520L, and V1279I, as well as previously reported mutations D1275N and R222Q. Of 15 SCN5A mutation carriers in our study, 14 (93%) manifested arrhythmia: supraventricular arrhythmia (13 of 15), including sick sinus syndrome (5 of 15) and atrial fibrillation (9 of 15), ventricular tachycardia (5 of 15), and conduction disease (9 of 15).

Conclusions: Mutations in SCN5A were detected in 1.7% of DCM families. Two-thirds (6 of 9) of all reported DCM mutations in SCN5A localize to the highly conserved homologous S3 and S4 transmembrane segments, suggesting a shared mechanism of disruption of the voltage-sensing mechanism of this channel leading to DCM. Not surprisingly, SCN5A mutation carriers show a strong arrhythmic pattern that has clinical and diagnostic implications.

Figure 1. Pedigrees in the Familial Cardiomyopathy Registry Containing SCN5A Mutations

Missense mutations are listed as pedigree identifiers above related family trees. Generations are denoted by Roman numerals. Probands for each pedigree are designated by a black arrow. The legend for pertinent clinical information is described below the pedigrees. DCM = dilated cardiomyopathy; ICD = implantable cardioverter-defibrillator.

Figure 2. SCN5A Sequencing Results of the Familial Cardiomyopathy Registry

(A) Chromatograms demonstrating heterologous peaks in nucleotide sequence. For this report, samples manifesting abnormal elution profile on the WAVE system were sequenced, and 4 new missense mutations were identified among our dilated cardiomyopathy (DCM) population. (B) Relative locations of all currently reported DCM missense mutations of SCN5A superimposed on a schematic of the SCN5A protein (7,8,10). Red denotes 5 total missense mutations identified within the Familial Cardiomyopathy Registry, including the 4 new mutations reported here and D1275N identified previously (7).

Figure 3. Early Arrhythmia in SCN5A Mutation Carriers

(A) Electrocardiogram of proband V1279I at the age of 47 years, showing atrial fibrillation and left bundle branch block. The left bundle branch block was accidentally found at a young age and followed for many years before the development of dilated cardiomyopathy. (B) Electrocardiogram of individual III-10 of family D1275N, showing atrial fibrillation when the patient had a normal left ventricular ejection fraction (74%) (see Table 1).