Identification of large gene deletions and duplications in KCNQ1 and KCNH2 in patients with long QT syndrome

Eddy, Carey-Anne, MacCormick, Judith M., Chung, Seo-Kyung, Crawford, Jackie R., Love, Donald R., Rees, Mark I., Skinner, Jonathan R. and Shelling, Andrew N. 2008. Identification of large gene deletions and duplications in KCNQ1 and KCNH2 in patients with long QT syndrome. Heart Rhythm 5 (9) , pp. 1275-1281. 10.1016/j.hrthm.2008.05.033

Full text not available from this repository.

Abstract

Background Sequencing or denaturing high-performance liquid chromatography (dHPLC) analysis of the known genes associated with the long QT syndrome (LQTS) fails to identify mutations in approximately 25% of subjects with inherited LQTS. Large gene deletions and duplications can be missed with these methodologies. Objective The purpose of this study was to determine whether deletions and/or duplications of one or more exons of the main LQTS genes were present in an LQTS mutation-negative cohort. Methods Multiplex ligation-dependent probe amplification (MLPA), a quantitative fluorescent approach, was used to screen 26 mutation-negative probands with an unequivocal LQTS phenotype (Schwartz score >4). The appropriate MLPA kit contained probes for selected exons in LQTS genes KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2. Real-time polymerase chain reaction was used to validate the MLPA findings. Results Altered exon copy number was detected in 3 (11.5%) patients: (1) an ex13-14del of the KCNQ1 gene in an 11-year-old boy with exercise-induced collapse (QTc 580 ms); (2) an ex6-14del of the KCNH2 gene in a 22-year-old woman misdiagnosed with epilepsy since age 9 years (QTc 560 ms) and a sibling with sudden death at age 13 years; and (3) an ex9-14dup of the KCNH2 gene in a 12 year-old boy (QTc 550 ms) following sudden nocturnal death of his 32-year-old mother. Conclusion If replicated, this study demonstrates that more than 10% of patients with LQTS and a negative current generation genetic test have large gene deletions or duplications among the major known LQTS susceptibility genes. As such, these findings suggest that sequencing-based mutation detection strategies should be followed by deletion/duplication screening in all LQTS mutation-negative patients.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > R Medicine (General)
Uncontrolled Keywords:	deletions, duplications, long QT syndrome, multiplex ligation-dependant probe amplification, arrhythmias
Publisher:	Elsevier
ISSN:	1547-5271
Last Modified:	05 Jul 2013 21:56
URI:	https://orca.cardiff.ac.uk/id/eprint/25280

Citation Data

Cited 71 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item