The cardiac sodium channel mutation delQKP 1507-1509 is associated with the expanding phenotypic spectrum of LQT3, conduction disorder, dilated cardiomyopathy, and high incidence of youth sudden death

Abstract

Aim: We report diverse phenotypic consequences of the delQKP-1507-1509 cardiac sodium channel mutation in three generations of a Chinese family.

Methods and results: Clinical and electrocardiographic (ECG), echocardiographic examination was followed by direct sequencing of SCN5A, KCNQ1, HERG, and LAMIN A/C to screen genomic DNA from blood samples. Of two mutation carriers, the proband was born with conduction disorders including second-degree atrioventricular (AV) block with prolonged QTc interval, additionally showing left anterior fascicular block (LAFB), incomplete right bundle-branch block (IRBBB), and intermittent third-degree AV block at 2 years, and clinical presentations of multiple syncope despite normal electroencephalograms at 8 years. Continuous ECG monitoring following presentation at 13 years revealed prolonged QTc and biphasic T-waves, multiple episodes of ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Transthoracal echocardiography then revealed left ventricular dilatation and reduced systolic function. Another mutation carrier showed features of long QT syndrome type 3 (LQT3), LAFB, and dilated cardiomyopathy (DCM). Two additional subjects died suddenly at 13 and 33 years.

Conclusion: This data compliments and expands the spectrum of phenotypes resulting from this known gain-of-function mutation, including not only LQT3, cardiac conduction defects, and sudden death but also DCM, hitherto associated with loss-of-function mutations, for the first time.

Figure 1

Pedigree information of the family with the SCN5A-delQKP1507–1509 mutation. Filled squares denote affected male; filled circles denote affected female; open squares denote unaffected males; open circles denote unaffected females; pen square with a slash indicates deceased because of liver cancer; filled circles/square with a slash indicates sudden death and genotypes consequently are not available. Arrows indicate the proband.

Figure 2

Twelve-lead electrocardiography (ECG) and transthoracal echocardiography results of proband. (A) 12-lead ECG (25 mm/s). Leads I, II, III, aVR, aVL, aVF (10 mm/mV), and V1–V6 (5 mV/mm) showed prolonged QTc, with the former showing biphasic T waves, and the latter alternating upright and inverting T-waves (T-wave alternans). ECG records also show intraventricular conduction delay of left anterior fascicular block (LAFB) and incomplete right bundle-branch block (IRBBB). (B) An example of an episode of torsades de pointes. (C) Transthoracal echocardiographic image demonstrating dilated left ventricle by apex position. (D) Colour Doppler image showed dysfunction of the left ventricular wall (wall velocity approximately 4.35 cm/s).

Figure 3

delQKP1507–1509 mutation of SCN5A sodium channel. (A) A heterozygous deletion of nine base pairs (CAGAAGCCC) in exon 26 of SCN5A resulting in the deletion of three amino acids QKP Gln1507–Lys1508–Pro1509 compared with the corresponding control segments (B) of exon 26 of SCN5A. (C) SSCP confirmed two mutation carriers (proband and subject I-2). No labelled bands are control samples. (D) Position of the delQKP1507–1509 mutation on Nav1.5 channel.