Risk of syncope in family members who are genotype-negative for a family-associated long-QT syndrome mutation.
Risk of syncope in family members who are genotype-negative for a family-associated long-QT syndrome mutation.
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DOI：
10.1161/circgenetics.111.960179
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发表时间：
2011-10
期刊：
影响因子：
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通讯作者：
Goldenberg I
中科院分区：
文献类型：
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作者：
Barsheshet A;Moss AJ;McNitt S;Polonsky S;Lopes CM;Zareba W;Robinson JL;Ackerman MJ;Benhorin J;Kaufman ES;Towbin JA;Vincent GM;Qi M;Goldenberg I
目前临床对长qt综合征（LQTS）的诊断包括对突变阳性患者的家庭成员进行基因检测。本研究旨在评估家族中lqts致病突变呈阴性的个体的临床病程。采用多变量Cox比例风险模型评估1828名来自LQTS登记处的患者从出生到40岁发生心脏事件（包括晕厥、流产性心脏骤停[ACA]或心源性猝死[SCD]）的风险，这些患者的家族LQTS致突变呈阴性。研究对象的QTc中位数为423 msec（四分位数范围：402-442 msec）。40岁期间首次晕厥的累积概率为15%。然而，只有2例患者（0.1%）出现ACA，随访期间无突然死亡。基因型阴性受试者晕厥的独立危险因素包括女性（HR 1.60, p = 0.002）、QTc延长（HR = 1.63 / 100 msec, p = 0.02）、ACA或SCD家族史（HR = 1.89, p = 0.002）、LQT2与LQT1家族突变（HR = 1.41, p = 0.03）。亚组分析显示，受影响家族中LQT2基因中K897T多态性的存在与基因型阴性受试者晕厥复发风险增加11倍（p = 0.001）相关。我们的研究结果表明，LQTS患者基因型阴性家庭成员的心脏事件以非致死性晕厥发作为主，未发生心源性猝死。该人群中非致命性事件的风险可能是由LQTS基因中常见多态性的存在介导的。
Current clinical diagnosis of long-QT syndrome (LQTS) includes genetic testing of family members of mutation positive patients. The present study was designed to assess the clinical course of individuals who are found negative for the LQTS-causing mutation in their families. Multivariate Cox proportional hazards model was used to assess the risk for cardiac events (comprising syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) from birth through age 40 years among 1828 subjects from the LQTS Registry who were found negative for their family LQTS-causing mutation. The median QTc of study subjects was 423 msec (interquartile-range: 402–442 msec). The cumulative probability of a first syncope through age 40 years was 15%. However, only 2 patients (0.1%) experienced ACA and none died suddenly during follow-up. Independent risk factors for syncope in genotype negative subjects included female gender (HR 1.60, p = 0.002), prolonged QTc (HR = 1.63 per 100 msec increment, p = 0.02), family history of ACA or SCD (HR = 1.89, p = 0.002), and LQT2 vs. LQT1 family mutation (HR = 1.41, p = 0.03). Subgroup analysis showed that the presence of the K897T polymorphism in the LQT2 gene in an affected family was associated with an 11-fold (p = 0.001) increase in the risk of recurrent syncope in genotype negative subjects. Our findings suggest that cardiac events among genotype-negative family members of LQTS patients are dominated by nonfatal syncopal episodes without occurrence of sudden cardiac death. The risk for nonfatal events in this population may be mediated by the presence of common polymorphisms in LQTS genes.