Chen S, Zhang L, Bryant R M, Vincent G M, Flippin M, Lee J C, Brown E, Zimmerman F, Rozich R, Szafranski P, Oberti C, Sterba R, Marangi D, Tchou P J, Chung M K, Wang Q
Center for Molecular Genetics, Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, OH 44195, USA.
Clin Genet. 2003 Apr;63(4):273-82. doi: 10.1034/j.1399-0004.2003.00048.x.
Long QT syndrome (LQTS) is the prototype of the cardiac ion channelopathies which cause syncope and sudden death. LQT1, due to mutations of KCNQ1 (KVLQT1), is the most common form. This study describes the genotype-phenotype characteristics in 10 families with mutations of KCNQ1, including 5 novel mutations. One hundred and two families with a history of lethal cardiac events, 55 LQTS, 9 Brugada syndrome, 18 idiopathic ventricular fibrillation (IVF), and 20 acquired LQTS, were studied by single-strand conformational polymorphism (SSCP) and DNA sequence analyzes. Families found to have KCNQ1 mutations were phenotyped using ECG parameters and cardiac event history, and genotype-phenotype correlation was performed. No mutations were found in Brugada syndrome, IVF, or acquired LQTS families. Ten out of 55 LQTS families had KCNQ1 mutations and 62 carriers were identified. Mutations included G269S in domain S5; W305X, G314C, Y315C, and D317N in the pore region; A341E and Q357R in domain S6; and 1338insC, G568A and T587M mutations in the C-terminus. W305X, G314C, Q357R, 1338insC, and G568A, appeared to be novel mutations. Gene carriers were 26 +/- 19 years (32 females). Baseline QTc was 0.47 +/- 0.03 s (range 0.40-0.57 s) and 40% had normal to borderline QTc (< or = 0.46 s). Typical LQT1 T wave patterns were present in at least one affected member of each family, and in 73% of all affected members. A history of cardiac events was present in 19/62 (31%), 18 with syncope, 2 with aborted cardiac arrest (ACA) and six with sudden death (SD). Two out of 6 SDs (33%) occurred as the first symptom. No difference in phenotype was evident in pore vs. non-pore mutations. KCNQ1 mutations were limited to LQTS families. All five novel mutations produced a typical LQT1 phenotype. Findings emphasize (1) reduced penetrance of QTc and symptoms, resulting in diagnostic challenges, (2) the problem of sudden death as the first symptom (33% of those who died), and (3) genetic testing is important for identification of gene carriers with reduced penetrance, in order to provide treatment and to prevent lethal cardiac arrhythmias and sudden death.
长QT综合征（LQTS）是导致晕厥和猝死的心脏离子通道病的典型代表。由于KCNQ1（KVLQT1）突变引起的LQT1是最常见的类型。本研究描述了10个携带KCNQ1突变的家系的基因型-表型特征，其中包括5种新突变。通过单链构象多态性（SSCP）和DNA序列分析，对102个有致死性心脏事件病史的家系进行了研究，其中55个为LQTS家系、9个为Brugada综合征家系、18个为特发性室颤（IVF）家系以及20个获得性LQTS家系。对发现携带KCNQ1突变的家系，采用心电图参数和心脏事件病史进行表型分析，并进行基因型-表型相关性研究。在Brugada综合征、IVF或获得性LQTS家系中未发现突变。55个LQTS家系中有10个携带KCNQ1突变，共鉴定出62名携带者。突变包括S5结构域的G269S；孔区的W305X、G314C、Y315C和D317N；S6结构域的A341E和Q357R；以及C末端的1338insC、G568A和T587M突变。W305X、G314C、Q357R、1338insC和G568A似乎是新突变。基因携带者的年龄为26±19岁（32名女性）。基线QTc为0.47±0.03秒（范围0.40 - 0.57秒），40%的携带者QTc正常至临界（≤0.46秒）。每个家系至少有一名受累成员出现典型的LQT1 T波形态，在所有受累成员中这一比例为73%。62名携带者中有19名（31%）有心脏事件病史，其中18名有晕厥，2名有心脏骤停未遂（ACA），6名有猝死（SD）。6例猝死中有2例（33%）以猝死为首发症状。孔区突变与非孔区突变在表型上无明显差异。KCNQ1突变仅限于LQTS家系。所有5种新突变均产生典型的LQT1表型。研究结果强调：（1）QTc和症状的外显率降低，导致诊断困难；（2）猝死作为首发症状的问题（33%的死亡者）；（3）基因检测对于识别外显率降低的基因携带者很重要，以便进行治疗并预防致死性心律失常和猝死。
