Roberts Jason D, Krahn Andrew D, Ackerman Michael J, Rohatgi Ram K, Moss Arthur J, Nazer Babak, Tadros Rafik, Gerull Brenda, Sanatani Shubhayan, Wijeyeratne Yanushi D, Baruteau Alban-Elouen, Muir Alison R, Pang Benjamin, Cadrin-Tourigny Julia, Talajic Mario, Rivard Lena, Tester David J, Liu Taylor, Whitman Isaac R, Wojciak Julianne, Conacher Susan, Gula Lorne J, Leong-Sit Peter, Manlucu Jaimie, Green Martin S, Hamilton Robert, Healey Jeff S, Lopes Coeli M, Behr Elijah R, Wilde Arthur A, Gollob Michael H, Scheinman Melvin M
For author affiliations, please see the Appendix.
Circ Arrhythm Electrophysiol. 2017 Aug;10(8). doi: 10.1161/CIRCEP.117.005282.
Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the -encoded voltage-gated channel β-subunit, is limited. We sought to further characterize its clinical phenotype.
Individuals with reported pathogenic mutations identified during arrhythmia evaluation were collected from inherited arrhythmia clinics and the Rochester long-QT syndrome (LQTS) registry. Previously reported LQT6 cases were identified through a search of the MEDLINE database. Clinical features were assessed, while reported mutations were evaluated for genotype-phenotype segregation and classified according to the contemporary American College of Medical Genetics guidelines. Twenty-seven probands possessed reported pathogenic mutations, while a MEDLINE search identified 17 additional LQT6 cases providing clinical and genetic data. Sixteen probands had normal resting QTc values and only developed QT prolongation and malignant arrhythmias after exposure to QT-prolonging stressors, 10 had other LQTS pathogenic mutations, and 10 did not have an LQTS phenotype. Although the remaining 8 subjects had an LQTS phenotype, evidence suggested that the variant was not the underlying culprit. The collective frequency of variants implicated in LQT6 in the Exome Aggregation Consortium database was 1.4%, in comparison with a 0.0005% estimated clinical prevalence for LQT6.
On the basis of clinical phenotype, the high allelic frequencies of LQT6 mutations in the Exome Aggregation Consortium database, and absence of previous documentation of genotype-phenotype segregation, our findings suggest that many variants, and perhaps all, have been erroneously designated as LQTS-causative mutations. Instead, variants may confer proarrhythmic susceptibility when provoked by additional environmental/acquired or genetic factors, or both.
对6型长QT综合征（LQT6）的认识有限，该综合征由编码电压门控通道β亚基的基因突变引起。我们试图进一步描述其临床表型。
从遗传性心律失常诊所和罗切斯特长QT综合征（LQTS）登记处收集在心律失常评估期间发现有报告的致病突变的个体。通过检索MEDLINE数据库确定先前报告的LQT6病例。评估临床特征，同时评估报告的突变以进行基因型-表型分离，并根据当代美国医学遗传学学会指南进行分类。27名先证者有报告的致病突变，而MEDLINE检索又确定了另外17例提供临床和遗传数据的LQT6病例。16名先证者静息QTc值正常，仅在暴露于延长QT的应激源后出现QT延长和恶性心律失常，10名有其他LQTS致病突变，10名没有LQTS表型。尽管其余8名受试者有LQTS表型，但证据表明该变异不是潜在病因。外显子聚合联盟数据库中与LQT6相关的变异的总体频率为1.4%，而LQT6的估计临床患病率为0.0005%。
基于临床表型、外显子聚合联盟数据库中LQT6突变的高等位基因频率以及先前缺乏基因型-表型分离的记录，我们的研究结果表明，许多变异，甚至可能所有变异，都被错误地指定为LQTS致病突变。相反，当受到额外的环境/获得性或遗传因素或两者的激发时，这些变异可能会导致心律失常易感性。
