Europace Advance Access published online on August 12, 2008
Europace, doi:10.1093/europace/eun202
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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
1 Department of Paediatrics, First Affiliated Hospital, Cardiovascular Ion Channel Disease Laboratory, Medical College of Xi'an Jiaotong University, Xi'an, Peoples Republic of China; 2 Department of Cardiology, First Affiliated Hospital, Cardiovascular Ion Channel Disease Laboratory, Medical College of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, Shaanxi 710061, Peoples Republic of China; 3 Cardiovascular Biology Group, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK; 4 Physiological Laboratory, University of Cambridge, Cambridge CB2 3EG, UK; 5 Medical College of Xi'an Jiaotong University, Xi'an, Peoples Republic of China
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.
Key Words: SCN5A, Mutation, LQT, Overlap phenotype, Dilated cardiomyopathy, Conduction disorder
* Corresponding author. Tel: +86 29 85323211. E-mail address: maaiqun{at}medmail.com.cn
Both the authors contributed equally to this paper.
Manuscript submitted 19 May 2008. Accepted after revision 4 July 2008.
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