Abstract 20290: Spectrum and Contribution of Mutations in Minor Long QT Syndrome (LQTS)-Susceptibility Genes in Patients Referred for FAMILION® LQTS Genetic Testing
Background: Inherited long QT syndrome (LQTS) is a potentially lethal arrhythmogenic syndrome marked by significant genetic heterogeneity. In recent years, several new genetic substrates for LQTS have been discovered, referred to as ‘minor’ LQTS genes to reflect their relatively infrequent contribution to the pathogenesis of LQTS. Here, we describe the spectrum and prevalence of mutations in patients referred for LQTS genetic testing in the 6 most recently identified minor LQTS-susceptibility genes.
Methods: DNA sequence analysis of 6 minor LQTS-susceptibility genes [KCNJ2 (LQT7), CACNA1C (LQT8), CAV3 (LQT9), SCN4B (LQT10), AKAP9 (LQT11), and SNTA1 (LQT12)] was performed for 850 unrelated patients referred for FAMILION LQTS genetic testing. Sequencing of CACNA1C and AKAP9 was restricted to exons in which LQTS-associated mutations have been reported previously.
Results: Overall, 37/850 (4.4%) patients hosted a possible LQTS-causing mutation in a minor LQTS gene (LQTS subtypes 7–12). Among these patients, 28 distinct mutations (25 novel) were identified: 4 in KCNJ2, 1 in CACNA1C, 4 in CAV3, 5 in SCN4B, 2 in AKAP9, and 12 in SNTA1. Of these distinct mutations, 24 were missense mutations, 3 were splice-site mutations, and 1 was a frameshift mutation resulting in premature protein truncation.
Conclusions: This study represents the largest collection of patients referred for LQTS genetic testing that have undergone systematic analysis of these minor LQTS-susceptibility genes, providing opportunities for further structure-function analyses to assess not only the pathogenicity of these novel variants but also the pathogenic mechanisms underlying LQT7–12. Expanding the LQTS genetic test to include these particular genes has increased the relative yield of FAMILION LQTS genetic testing by 10%.
- © 2010 by American Heart Association, Inc.