DOES MUTATION LOCATION AFFECT SEVERITY OF PHENOTYPE IN TYPE 1 LONG QT SYNDROME? IMPACT OF TRANSMEMBRANE AND C-LOOP LOCATION

BACKGROUND: Examination of genotype-phenotype correlation is important for the management of patients with congenital LQTS1. Precise targeted mutation site-specific differences have correlated C-loop missense mutations with worse outcomes and increased benefit of beta blockers. Corresponding cellular expression studies have implicated the C-loop region as mechanistically important in the altered response to sympathetic stimulation that triggers events in LQT1. OBJECTIVE: Determine if there is a clinically detectable difference in KCNQ1 channel mutation site specific response to sympathetic stimulation using graded exercise stress testing (GXT). METHODS: A retrospective review of LQT1 patients undergoing GXT at a pediatric and adult regional referral center was undertaken (2002-2011). Only patients with disease-causing mutations were included. QT intervals and heart rate were recorded supine at rest, immediately upon standing, at early exercise, peak exercise, 1 minute into recovery, and 4 minutes into the recovery phase. The QTc was calculated using the Bazett formula. Results are listed as mean 95% confidence interval. RESULTS: Sixty-seven genetically characterized LQT1 patients were identified (6-67 years of age, 52% female, 16 pediatric and 51 adults patients). Mutations consisted of 3 N-terminus, 36 membrane spanning, 15 c-loop, and 13 c-terminus locations. The supine QTc was prolonged at rest (464 33 msec), and increased upon immediate standing (498 36 msec), in early exercise (504 41 msec), and at peak exercise (525 46 msec). During recovery, the QTc remained markedly prolonged at 504 51 msec at 1 minute and 500 41 msec at 4 minutes. There were no statistically significant differences in QTc between patients with c-loop mutations and patients with alternate sites of mutations in any of the recorded QTc intervals.