P2865Mutation specific clinical characteristics in long QT syndrome type 8; severe phenotype in Timothy syndrome patients

Abstract

Abstract Background Long QT syndrome type 8 (LQT8) caused by mutations in CACNA1C has been classified as a very rare and severe type of long QT syndrome accompanied with Timothy syndrome (TS) with extra-cardiac phenotype. Recently, various mutations in CACNA1C have been identified in non-TS patients. However, mutation specific severity in LQT8 has not been elucidated yet, especially for non-TS patients. Purpose We aimed to clarify the clinical characteristics of LQT8 patients. Methods The study consists of 26 LQT8 patients (21 probands and 5 family members). We evaluated their phenotype. Results Table summarizes the clinical characteristics of LQT8 patients. TS patients diagnosed in younger age than those of non-TS. Four TS and one non-TS patients were diagnosed at the age of 0, though the non-TS patient was a son of a patient and asymptomatic. Nine patients suffered symptoms including 7 with cardiac arrest. We identified three TS mutations; classical p.G406R in two and p.G402S in two, and a new TS mutation, p.412M in one. Four of TS patients were symptomatic and two died suddenly at the age of 4 and 5. In contrast, no one died in non-TS patients. Five non-TS patients suffered symptoms in the age of 4,9,15,54 and 64, and the mutations were p.S643F, p.R858H (2 patients), p.K1518E and p.K1591T. Characteristics of TS and non-TS patient TS Non-TS P N (male) 5 (2) 21 (9) Age (range) 0 (0–7) 12 (0–64) 0.004 Symptom Syncope 4 5 0.034 CPA 3 4 0.101 ECG characteristics QT interval 603±40 507±14 0.011 T wave alternans 5 2 <0.001 AV Block 4 1 0.002 Therapy (4 unknown) Beta-blocker 4 7 0.311 Mexiletine 3 1 0.024 ICD implantation 2 2 0.21 Conclusions Although TS patients showed severe phenotype, most of the non-TS patients were asymptomatic. The phenotype in LQT8 are diversely different depend on the mutations, especially between patients with TS and non-TS.