3型长QT综合征基因突变型与表型关系分析  

Mutation-Specific Genotype-Phenotype Correlations in Long QT Syndrome Type 3

作　　者：李翠兰[1] 李旭 郭保静[2] 王福军 梁璐[4] 蒋勇 高元丰 李蕾[1] 胡大一[1] 刘文玲[1] LI Cuilan;LI Xu;GUO Baojing;WANG Fujun;LIANG Lu;JIANG Yong;GAO Yuanfeng;LI Lei;HU Dayi;LIU Wenling(Department of Cardiology,Peking University People’s Hospital,Beijing 100044,China;Department of Pediatric Heart Center,Beijing Anzhen Hospital,Capital Medical University,Beijing 100029,China;Department of Cardiology,People’s Hospital of Xiangxi Tujia and Miao Autonomous Prefecture,Jishou 416000,Hunan,China;Division of Pediatric Cardiology,Capital Institute of Pediatrics,Beijing 100020,China;Heart Center,Beijing Chaoyang Hospital,Capital Medical University,Beijing 100020,China)

机构地区：[1]北京大学人民医院心内科,北京100044 [2]首都医科大学附属北京安贞医院小儿心脏中心心内科,北京100029 [3]湘西土家族苗族自治州人民医院心内科,湖南吉首416000 [4]首都儿科研究所小儿心脏病科,北京100020 [5]首都医科大学附属北京朝阳医院心脏中心,北京100020

出　　处：《心血管病学进展》2023年第9期853-857,864,共6页Advances in Cardiovascular Diseases

基　　金：国家自然科学基金(81170089)。

摘　　要：目的 目前已发现至少17个先天性长QT综合征(LQTS)亚型,其中3型长QT综合征(LQT3)检出率为5%~10%,占第三位。该型人数虽不是很多,但由于症状严重、发生猝死的风险高而备受关注。现探讨中国LQT3患者特定突变型与表型的关系。方法 共入组6例2001—2014年诊断为LQT3的先证者。用新一代靶向技术和直接测序法或全外显子测序法检测到SCN5A基因上的突变。对携带特定突变的先证者及其受累亲属进行突变型和表型分析。结果 共检出SCN5A上的5个致病突变(V411M、P1332L、F1473S、R1644H和delD1790)。表型分析显示,多数先证者具有典型的LQT3型心电图(ECG)特点,美西律治疗有效。2例携带V411M突变的无关联先证者均表现为窦性心动过速,且不能被β受体阻滞剂抑制。携带P1332L突变的先证者表现出类似LQT2型的ECG模式,对美西律敏感。1例携带F1473S突变的患者在出生不久即发生了首次心脏事件,美西律无效,2.5岁时发生猝死。携带纯合R1644H突变的患者ECG上表现为基底部宽大的倒置T波,足量美西律治疗后可使ECG完全正常化。另外观察到位于C末端的delD1790突变引起致死性心脏事件的风险低。结论 LQT3患者发生心脏事件的风险与其携带突变位置及是否在出生后第1年内有症状有关。这些发现为进一步研究中国人LQT3患者的基因突变型与表型关系提供了更多的证据。Objective Congenital long QT syndrome type 3(LQT3),which accounts for 5%~10%,is the third in frequency among 17 currently known forms of congenital long QT syndrome(LQTS).Although the number of patients with this type is not large,it has attracted attention due to its severe symptoms and high risk of sudden death.This study aimed to explore the mutation-specific genotype-phenotype correlations in Chinese patients with LQT3.Methods We enrolled six probands with a clinical diagnosis of LQT3 between 2001 and 2014.Mutations in SCN5A were identified by direct sequencing and targeted next-generation/whole-exome sequencing.Phenotypes and genotypes of the probands with certain mutations and their affected relatives were evaluated.Results Five pathogenic mutations(V411M,P1332L,F1473S,R1644H and delD1790) were identified in SCN5A.Phenotype analysis showed that most probands had typical LQT3 electrocardiogram(ECG) patterns and could be protected by mexiletine therapy.The V411M mutation in two unrelated probands might be associated with sinus tachycardia,which could not be suppressed by β-blockers.The proband carrying the P1332L mutation showed an LQT2-like ECG pattern and was sensitive to mexiletine.One patient carrying F1473S who had her first cardiac event in the first year of life,died at the age of 2.5 years.Broad base inverted T waves were observed in the patient carrying the homozygous R1644H missense mutation that was normalized by mexiletine.Additionally,the delD1790 mutation localized in the C-terminus confers a lower risk for life-threatening events.Conclusion The risk of cardiac events in LQT3 patients varies according to the location of the mutations and symptoms in the first year of life.This study broadens the genotype-phenotype spectra of LQT3 patients in China.These findings provide more evidences for further investigation of the genotype-phenotype relationships in Chinese LQT3 patients.

关 键 词：3型长QT综合征 SCN5A基因突变 基因型-表型关系 

分 类 号：R541[医药卫生—心血管疾病]