Abstract 2194: Predictors of RyR2 Genotype Among Patients Referred for Long QT Syndrome Genetic Testing

Abstract

Listen

Translate article

Introduction : Type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1) is pursuant to mutations in the RyR2- encoded cardiac ryanodine receptor. Recently, we discovered nearly as many CPVT1-causing mutations as LQT3-causing mutations in a large cohort of unrelated LQTS referral patients. Here, we examine potential predictors of RyR2 genotype (CPVT1) among LQTS referral patients. Methods : Previously, comprehensive mutational analysis of the LQT1–10 susceptibility genes was completed for 541 unrelated patients (358 females, average age at diagnosis = 24 years, average QTc = 482 ms) referred for LQTS genetic testing. Using PCR, DHPLC, and DNA sequencing, we performed targeted analysis of RyR2 involving 44 exons (8–15, 37–49, 83–105) for the 260 unrelated referrals (172 females, average age at diagnosis = 25 years, average QTc = 470 ms) that remained “genotype-negative” following LQTS genetic testing. Results : Overall, 22 distinct RyR2 mutations (19 novel) were seen in 23 (8.8%, 12 females, average age at diagnosis = 22 ±14 years) unrelated “genotype-negative” LQTS individuals. Compared to patients with either genetically proven LQTS or the remaining genotype negative cohort, the RyR2 -positive cohort had significantly lower average QTc (419 ms vs 494 ms, p =2.4 ×10 −6 ; vs 472 ms, p = 0.005) and was more likely to experience either syncope (88% vs 66%, p = 0.06 vs 53%, p = 0.008) or cardiac arrest (56% vs 23%, p = 0.006 vs 17%, p = 0.001). Overall, 123 of the 541 LQTS referrals (23%) exhibited exertion-induced cardiac events (68 LQTS gene positive; 42 gene negative, and 13 RyR2-positive). Every RyR2 -positive case with an exertionally-triggered event had a QTc ≤ 460 ms, compared to only 17% of LQTS gene positive cases (p = 0.1 × 10 −8 ) and 24% of LQT1 cases. None of the exertion-induced LQTS gene positive cases had a QTc ≤ 420 ms. Conclusions: Failure to distinguish CPVT from LQTS can be a fatal mistake, as individuals with CPVT1 have a more severe phenotype and are much less protected by beta blocker therapy than those with LQT1. CPVT1, rather than concealed LQT1, should lead the differential diagnosis in the setting of syncope/cardiac arrest during exercise and a normal resting QTc.