Abstract 16277: Absence of Putative Long QT Syndrome (LQTS)-Causing Mutations in the KCNJ5-Encoded Kir3.4 Channel Among a Large Cohort of Unrelated Patients With LQT1-12 Genotype Negative/Phenotype Positive LQTS
Background: Long QT syndrome is a potentially lethal heritable arrhythmia disorder characterized by delayed cardiac repolarization and prolongation of QT interval on a 12-lead ECG. Approximately 75% of LQTS stems from mutations in 3 genes that encode critical cardiac channel alpha subunits: KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3). Recently, a missense mutation (G387R) was identified in a single large Chinese LQTS family using genome-wide linkage analysis, implicating KCNJ5 as the 13th LQTS-susceptibility gene discovered to date. However, the relative contribution of KCNJ5-LQTS (LQT13) remains unknown.
Methods: This IRB-approved study involved DNA isolated from 62 unrelated patients (40 females, average age at diagnosis 23±15 years, average QTc 534±64 ms) who were clinically diagnosed with LQTS and had a QTc≥480 ms but were LQT1-12 genotype negative. Using PCR, DHPLC, and DNA sequencing, KCNJ5's open reading frame was analyzed for mutations in its encoded, 419-amino acid containing, Kir3.4 acetycholine-sensitive potassium channel. DNA from 200 healthy control subjects (100 white and 100 black) was obtained from the Coriell Cell Repository.
Results: Despite having a large LQT1-12 negative cohort of unrelated patients for gene discovery, no putative LQT13-associated mutations were detected. Instead, 3/62 (4.8%) cases had the non-synonymous single nucleotide common polymorphism, Q282E, that was seen with a similar frequency (5.6%) among reportedly healthy Caucasians. This polymorphism was not detected in 100 African American controls. In addition, a rare amino acid substitution, D262N, was identified in a reportedly healthy black control.
Conclusions: Mutations in KCNJ5 (LQT13) represent an extremely rare form of LQTS, at least among Caucasians. Given the extreme rarity of this LQTS-susceptibility gene and some of the other minor LQTS-susceptibility genes, caution must be exercised regarding the continued expansion of the clinical LQTS genetic test. Inclusion of the minor LQTS genotypes like LQT13 is associated not only with a negligible positive impact on the yield of LQTS genetic testing but also a potentially detrimental impact of increasing the test's background genetic noise.
- © 2011 by American Heart Association, Inc.