Abstract 17866: A Novel Mutation in α-1 Syntrophin Associated with QT Prolongation, Left Ventricular Noncompaction and Dilated Cardiomyopathy
Background: Long-QT Syndrome (LQTS) is characterized by prolongation of QT interval and presence of syncope, seizures, and sudden death. Recently, we showed mutations in α-1 syntrophin (SNTA1), a member of dystrophin-associated protein complex, can cause LQTS type 12 by affecting cardiac Na+ channel (SCN5A) function. In addition, deficiency of SNTA1 is associated with muscular dystrophy but not with cardiomyopathy.
Methods and Results: Genetic screening for LQTS types 1 through 12 was performed in a previously healthy 21 year-old African American male who presented with seizures and a QTc interval of 557 msec. A novel missense mutation in SNTA1 (p.S223L) was identified. p.S223L was not observed in 5,000 individuals listed in the NHLBI ESP Exome Variant Server. The effect of p.S223L on INa was studied using the patch clamp technique on HEK-293 cells stably expressing SCN5A and transiently transfected with either wild-type or mutant SNTA1. p.S223L did not affect the peak INa compared to wild type ( -150.4 ± 22.5 pA/pF, n = 10, vs. -144.9 ± 25.2 pA/pF, n = 11). Voltage-dependency of steady state-activation and inactivation, and the late INa were also unaffected. On the other hand, the patient’s ECG revealed broad-based T waves and no rate adaptive QT shortening consistent with a LQT1 phenotype. The QT/RR slope was analyzed using simple linear regression yielding a slope of 0.06. The slope (r) was less steep than healthy subjects (r=0.42, n=33), and was similar to genetically identified LQT1 patients (r= 0.13, n=51 from 29 unrelated families). Interestingly, the patient’s QT intervals were shorter when he was 12 years old, and the QT/RR slope during an exercise test was much steeper than what it is now (QTc 468 msec, r=0.51). An echocardiogram showed prominent trabeculations of the left ventricle (LV) and a severely reduced LV systolic function. He underwent an ICD implantation and was successfully resuscitated from multiple VF episodes.
Conclusion: We identified a novel mutation in SNTA1 in a patient with marked QT prolongation, LV non-compaction and dilated cardiomyopathy. Our data indicates that p.S223L may affect KCNQ1 rather than SCN5A. Moreover, p.S223L may affect the stability of dystrophin-associated protein complex which may account for the cardiomyopathy.
- © 2012 by American Heart Association, Inc.