Advances in molecular genetics of long QT syndrome and summary of gene variants in Chinese
-
摘要: 长QT综合征(LQTS)是首个被发现的心脏离子通道病，是引起青少年猝死的重要原因，包括先天性LQTS(cLQTS)和获得性LQTS(aLQTS)。已经发现了至少17个致病基因，但根据欧洲/美国/亚太/拉美心律学会最新发布的2022版心脏病基因检测专家共识，只建议对其中11个证据明确的基因进行临床常规检测。本文就17个LQTS亚型的分子致病机制及其特征性临床表现的最新进展进行综述，并对已报道的国人LQTS基因变异进行总结，最后讨论分子遗传学检测在LQTS诊断治疗中的作用。Abstract: Long QT syndrome(LQTS), the first discovered cardiac channelopathy, is an important cause of sudden death in adolescents, including congenital LQTS(cLQTS) and acquired LQTS(aLQTS). At least 17 disease-causing genes have been identified, but according to the 2022 edition of the "Expert Consensus on Genetic Testing for Heart Disease" released by the European/American/Asia-Pacific/Latin American Heart Rhythm Society, routine testing of only 11 of these genes with clear evidence is recommended. In this paper, the molecular pathogenesis mechanism and characteristic clinical manifestations of 17 LQTS subtypes are reviewed, and the reported LQTS gene variants of Chinese people are summarized, and the role of genetic test in the diagnosis and treatment of LQTS is finally discussed.
-
-
表 1 证据明确的LQTS致病基因
Table 1. LQTS pathogenic genes with clear evidences
基因 位点 表型-综合征 蛋白 电流(功能效应) 占比 ClinGen分类 KCNQ1 11p15.5 LQT1，JLNS KCNQ1(Kv7.1) IKs(↓) 40%~55% 证据明确 KCNH2 7q35-36 LQT2 hERG(Kv11.1) IKr(↓) 30%~45% 证据明确 SCN5A 3p21-p24 LQT3 Nav1.5 INa1.5(↑) 5%~10% 证据明确 CALM1 14q32.11 LQT14 Calmodulin ICa-L(↑) < 1% 证据明确 CALM2 2p21 LQT15 Calmodulin ICa-L(↑) < 1% 证据明确 CALM3 19q13.32 LQT16 Calmodulin ICa-L(↑) < 1% 证据明确 TRDN 6q22.31 LQT17(TKOS) Triadin ICa-L(↑) < 1% 强证据 KCNE1 21q22.1 LQT5，JLNS，a-LQTS KCNE1(minK) IKs(↓) < 1% 在aLQTS强证据，
在JLNS证据明确KCNE2 21q22.1 LQT6，a-LQTS KCNE2(MiRP1) IKr(↓) < 1% 在aLQTS强证据 KCNJ2 17q24.3 LQT7，ATS Kir2.1 IK1(↓) < 1% 在ATS证据明确 CACNA1C 12p13.3 TS，LQT8 Cav1.2 ICa-L(↑) < 1% 在TS证据明确，
在LQTS中等证据
下载: 导出CSV
表 2 证据有限的LQTS致病基因
Table 2. LQTS pathogenic genes with limited evidences
基因 染色体座位 综合征 蛋白 电流(功能效应) 占比 ClinGen分类 ANK2 4q25-q27 LQT4 Ankyrin-B NaV1.5(↑) < 1% 有争议 CAV3 3p25 LQT9 Caveolin 3 NaV1.5(↑) < 1% 证据有限 SCN4B 11q23.3 LQT10 Nav1.5 β4 NaV1.5(↑) < 1% 有争议 AKAP9 7q21-q22 LQT11 AKAP-9(yotiao) Ik(↓) < 1% 有争议 SNTA1 20q11.2 LQTS12 α1-Syntrophin NaV1.5(↑) < 1% 有争议 KCNJ5 11q24.3 LQT13 Kir3.4(GIRK4) Kir3.4(↓) < 1% 有争议
下载: 导出CSV
-
[1] Nader A, Massumi A, Cheng J, et al. Inherited arrhythmic disorders: long QT and Brugada syndromes[J]. Tex Heart Inst J, 2007, 34(1): 67-75.
[2] Priori SG, Blomstrom-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology(ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology(AEPC)[J]. Eur Heart J, 2015, 36(41): 2793-2867. doi: 10.1093/eurheartj/ehv316
[3] Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management[J]. Circ Arrhythm Electrophysiol, 2012, 5(4): 868-877. doi: 10.1161/CIRCEP.111.962019
[4] Nakano Y, Shimizu W. Genetics of long-QT syndrome[J]. J Hum Genet, 2016, 61(1): 51-55. doi: 10.1038/jhg.2015.74
[5] Wallace E, Howard L, Liu M, et al. Long QT syndrome: genetics and future perspective[J]. Pediatr Cardiol, 2019, 40(7): 1419-1430. doi: 10.1007/s00246-019-02151-x
[6] 浦介麟, 张开滋, 李翠兰, 等. 遗传性心律失常[M]. 北京: 人民卫生出版社, 2010: 137-179.
[7] 李翠兰, 刘文玲, 高元丰. 先天性与获得性长QT综合征诊断治疗现状[J]. 心血管病学进展, 2021, 42(5): 385-391. doi: 10.16806/j.cnki.issn.1004-3934.2021.05.001
[8] Wilde AAM, Semsarian C, Márquez MF, et al. European Heart Rhythm Association(EHRA)/Heart Rhythm Society(HRS)/Asia Pacific Heart Rhythm Society(APHRS)/Latin American Heart Rhythm Society(LAHRS)Expert Consensus Statement on the state of genetic testing for cardiac diseases[J]. Europace, 2022, 24(8): 1307-1367. doi: 10.1093/europace/euac030
[9] Bohnen MS, Peng G, Robey SH, et al. Molecular pathophysiology of congenital long QT syndrome[J]. Physiol Rev, 2017, 97(1): 89-134. doi: 10.1152/physrev.00008.2016
[10] Chen L, Kurokawa J, Kass RS. Phosphorylation of the A-kinase-anchoring protein Yotiao contributes to protein kinase A regulation of a heart potassium channel[J]. J Biol Chem, 2005, 280: 31347-31352. doi: 10.1074/jbc.M505191200
[11] Zhang L, Timothy KW, Vincent GM, et al. Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes[J]. Circulation, 2000, 102(23): 2849-2855. doi: 10.1161/01.CIR.102.23.2849
[12] Giudicessi JR, Ackerman MJ. Genotype-and phenotype-guided management of congenital long QT syndrome[J]. Curr Probl Cardiol, 2013, 38(10): 417-455. doi: 10.1016/j.cpcardiol.2013.08.001
[13] Ono M, Burgess DE, Schroder EA, et al. Long QT syndrome type 2: emerging strategies for correcting class 2 KCNH2(hERG)mutations and identifying new patients[J]. Biomolecules, 2020, 10(8): 1144. doi: 10.3390/biom10081144
[14] Roberts JD, Krahn AD, Ackerman MJ, et al. Loss-of-function KCNE2 variants: true monogenic culprits of Long-QT syndrome or proarrhythmic variants requiring secondary provocation?[J]. Circ Arrhythm Electrophysiol, 2017, 10(8): e005282. doi: 10.1161/CIRCEP.117.005282
[15] Boczek NJ, Gomez-Hurtado N, Ye D, et al. Spectrum and prevalence of CALM1-, CALM2-, and CALM3-encoded calmodulin variants in long QT syndrome and functional characterization of a novel long QT syndrome-associated calmodulin missense variant, E141G[J]. Circ Cardiovasc Genet, 2016, 9(2): 136-146. doi: 10.1161/CIRCGENETICS.115.001323
[16] Clemens DJ, Tester DJ, Marty I, et al. Phenotype-guided whole genome analysis in a patient with genetically elusive long QT syndrome yields a novel TRDN-encoded triadin pathogenetic substrate for triadin knockout syndrome and reveals a novel primate-specific cardiac TRDN transcript[J]. Heart Rhythm, 2020, 17(6): 1017-1024. doi: 10.1016/j.hrthm.2020.01.012
[17] Sarquella-Brugada G, Fernandez-Falgueras A, Cesar S, et al. Pediatric malignant arrhythmias caused by rare homozygous genetic variants in TRDN: a comprehensive interpretation[J]. Front Pediatr, 2021, 8: 601708. doi: 10.3389/fped.2020.601708
[18] Swayne LA, Murphy NP, Asuri S, et al. Novel variant in the ANK2 membrane-binding domain is associated with Ankyrin-B syndrome and structural heart disease in a first nations population with a high rate of long QT Syndrome[J]. Circ Cardiovasc Genet, 2017, 10(1): e001537. doi: 10.1161/CIRCGENETICS.116.001537
[19] Pérez-Riera AR, Barbosa-Barros R, Samesina N, et al. Andersen-tawil syndrome: a comprehensive review[J]. Cardiol Rev, 2021, 29(4): 165-177. doi: 10.1097/CRD.0000000000000326
[20] Kokunai Y, Nakata T, Furuta M, et al. A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1[J]. Neurology, 2014, 82(12): 1058-1064. doi: 10.1212/WNL.0000000000000239
[21] Yang Y, Yang Y, Liang B, et al. Identification of a Kir3.4 mutation in congenital long QT syndrome[J]. Am J Hum Genet, 2010, 86(6): 872-880. doi: 10.1016/j.ajhg.2010.04.017
[22] Aiba T. Recent understanding of clinical sequencing and gene-based risk stratification in inherited primary arrhythmia syndrome[J]. J Cardiol, 2019, 73(5): 335-342. doi: 10.1016/j.jjcc.2019.01.009
[23] Garg P, Oikonomopoulos A, Chen H, et al. Genome editing of induced pluripotent stem cells to decipher cardiac channelopathy variant[J]. J Am Coll Cardiol, 2018, 72(1): 62-75. doi: 10.1016/j.jacc.2018.04.041
-
附件下载
全部国人突变汇总（共229个) 
-